Pyridylpyrimidine derivatives as effective compounds against prion diseases

ABSTRACT

The present invention relates to pyridylpyrimidine derivatives of the general formula (I):  
                 
 
     wherein R represents hydrogen or methyl and Z represents nitrogen containing functional groups, the use of the pyridylpyrimidine derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of prion infections and prion diseases, as well as compositions containing at least one pyridylpyrimidine derivative and/or pharmaceutically acceptable salt thereof. Furthermore, the present invention is directed to methods for preventing and/or treating prion infections and prion diseases using said pyridylpyrimidine derivatives. Human cellular protein kinases, phosphatases and cellular signal transduction molecules are disclosed as targets for detecting, preventing and/or treating prion infections and diseases, especially BSE, vCJD, or CJD which can be inhibited by the inventive pyridylpyrimidine derivatives.

[0001] The present invention relates to pyridylpyrimidine derivatives,the use of the pyridylpyrimidine derivatives as pharmaceutically activeagents, especially for the prophylaxis and/or treatment of prioninfections and prion diseases, as well as compositions containing atleast one pyridylpyrimidine derivative and/or pharmaceuticallyacceptable salt thereof, and methods for preventing and/or treatingprion infections and prion diseases. Furthermore, human cellular proteinkinases, phosphatases and cellular signal transduction molecules aredisclosed as targets for detecting, preventing and/or treating prioninfections and diseases, especially BSE, vCJD, or CJD.

BACKGROUND OF THE INVENTION

[0002] Pyridylpyrimidine derivatives are known from WO 9509851 aseffective compounds for chemotherapy of tumors, from WO 9509853, EP-A-0588 762, WO 9509847, WO 9903854, and EP-B-0 564 409 as effectivecompounds for treatment of tumors. Furthermore, EP-B-0 564 409 disclosesthe use of said compounds in the treatment of artherosclerosis and Exp.Opin. Ther. Patents, 1998, 8(12), 1599-1625 describes the use ofpyridylpyrimidine derivatives, especially of Gleevec™, the Novartiscompound CGP 57148, as tyrosine kinase inhibitors in cancer treatment.

[0003] Prions are infectious agents which do not have a nucleic acidgenome. It seems that a protein alone is the infectious agent. A prionhas been defined as “small proteinaceous infectious particle whichresists inactivation by procedures that modify nucleic acids”. Thediscovery that proteins alone can transmit an infectious disease hascome as a considerable surprise to the scientific community. Priondiseases are often called “transmissible spongiform encephalopathies”,because of the post mortem appearance of the brain with large vacuolesin the cortex and cerebellum. Probably most mammalian species developthese diseases. Prion diseases are a group of neurodegenerativedisorders of humans and animals and the prion diseases can manifest assporadic, genetic or infectious disorders. Examples for prion diseasesacquired by exogenous infection are the Bovine spongiform encephalitis(BSE) of cattle and the new variant of Creutzfeld-Jakob disease (vCJD)caused by BSE. Further examples include kuru,Gerstmann-Sträussler-Scheinker disease of humans as well as scrapie ofanimals. For many years, the prion diseases were thought to be caused byviruses despite intriguing evidence to the contrary. The uniquecharacteristic common to all of these disorders, whether sporadic,dominantly inherited, or acquired by infection, is that they involve theaberrant metabolism of the prion protein (PrP). In many cases, thecellular prion protein (PrP^(c)) [“c” refers to cellular] is convertedinto the scrapie isoform (PrP^(Sc)) [“Sc” refers to Scrapie] by aposttranslational process that involves a conformational change. Often,the human prion diseases are transmissible to experimental animals andall of the inherited prion diseases segregate with PrP gene mutations.

[0004] These prion diseases in animals and humans have a long incubationperiod and a long clinical course, and are always fatal leading viadecerebration to death within an average period of 7 months (CJD).Neuropathological features consist of neuronal vacuolization, neuronaldeath and gliosis with hyperastrocytosis. The precise diagnosis oftransmissible neurodegenerative diseases can be established only by theexamination of the central nervous system after biopsy or autopsy.

[0005] Clinical symptoms of the disease are progressive dementia,myoclonus and prominent ataxia with the additional clinical features ofdysautonomia and delirious psychomotor excitement and with relativelypreserved verbal responses.

[0006] Between 1980 and, roughly, 1996, about 750,000 cattle infectedwith BSE were slaughtered for human consumption in Great Britain(Anderson, R. M. et al. Nature 382, 779-788,1996; Ferguson, N. M.,Donnelly, C. A., Woolhouse, M. E. J. & Anderson, R. M. Phil. Trans. R.Soc. Lond. B 352, 803-838, 1997). The annual incidence of vCJD (3, 10,10, 18, 14 and 33 deaths in 1995-2000, respectively) can be interpretedas a first sign of a steady or exponential increase over the next years.The suggestion by the European Union Scientific Steering Committee thatup to 500,000 people could have been exposed to BSE from a singleinfected bovine has fuelled speculation that millions of consumers areat risk.

[0007] Recent findings demonstrate that the pathogenic PrP^(Sc) of vCJDcan be found in the lymph system (e.g. tonsils, lymph nodes) in humanssuggesting a high risk of horizontal spread via lymph and/or bloodtransmission, dramatically increasing the number of people at risk.

[0008] The medical need in prion diseases today can be clearly definedas the establishment of a diagnostic system, that can detect the diseaseas early as possible in living humans and/or animals, to estimate themedical need for the treatment in the future and to identify theinfected animals to remove them from the food chain. The medical needfor prion diseases in the future (approximately starting in 5-10 years)will be medical treatment that inhibits the disease symptoms, themanifestation and/or progression of the disease.

[0009] It is object of the present invention to provide novel and alsoknown compounds which can be used as pharmaceutically active agents,especially for prophylaxis and/or treatment of prion infections andprion diseases, methods wherein said compounds are used in order totreat prion infections and prion diseases and compositions containing atleast one inventive compound and/or pharmaceutically acceptable saltthereof as a pharmaceutically active ingredient.

[0010] The object of the present invention is solved by the teaching ofthe independent claims. Further advantageous features, aspects anddetails of the invention are evident from the dependent claims, thedescription, the examples, and the figures of the present application.

DESCRIPTION OF THE INVENTION

[0011] One aspect of the present invention is related to compounds ofthe general formula (I):

[0012] wherein:

[0013] R represents hydrogen or methyl;

[0014] Y, Y′, Y″ are independently of each other —H, —F, —Cl, —Br, —I,—CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —OH, —OCH₃, —CH₃, —CN, —OCF₃,4-methylpiperazin-1-yl-methyl, —C(CH₃)═N—NH—C(NH)—NH₂;

[0015] Z represents —NO₂, —NH₂, —NH—CO—X, —NH—CS—X, —NH—CO—NH—X,—NH—SO₂—X;

[0016] X represents thiophenyl, cyclohexyl, isoquinolinyl, naphthyl,quinolinyl, cyclopentyl, pyridinyl, naphthyridinyl, or

[0017] and pharmaceutically acceptable salts thereof.

[0018] Another aspect of the present invention relates to the use ofcompounds of the general formula (I):

[0019] wherein:

[0020] R represents hydrogen or methyl;

[0021] Y, Y′, Y″ are independently of each other —H, —F, —Cl, —Br, —I,—CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —OH, —OCH₃, —CH₃, —CN, —OCF₃,4-methylpiperazin-1-yl-methyl, —C(CH₃)═N—NH—C(NH)—NH₂;

[0022] Z represents —NO₂, —NH₂, —NH—CO—X, —NH—CS—X, —NH—CO—NH—X,—NH—SO₂—X;

[0023] X represents thiophenyl, cyclohexyl, isoquinolinyl, naphthyl,quinolinyl, cyclopentyl, pyridinyl, naphthydinyl, or

[0024] and pharmaceutically acceptable salts thereof as pharmaceuticallyactive agents, especially for prophylaxis and/or treatment of infectiousdiseases, or in a more general sense, for prophylaxis and/or treatmentof nerodegenerative diseases.

[0025] Thus, one embodiment of the present invention disclosed herein isdirected to a method for preventing and/or treating infections and/ordiseases associated with said infections in an individual. Said methodcomprises administering to the individual an amount of at least onecompound according to general formula (I) and/or pharmaceuticallyacceptable salts thereof effective to prevent and/or treat saidinfections and/or diseases. Most preferred is the administration of acompound 53.

[0026] As revealed for the first time herein, the present inventiondiscloses the use of compounds of the general formula (I) for theprophylaxis and/or treatment of prion infections and prion diseases. Asdescribed above, said pyridylpyrimidine derivatives have first of allbeen used in tumor therapy. The Novartis compound Gleevec™ also known asGlivec™, CGP-57148B, imatinib mesylate, STI-571, STI-571A, CAS152459-95-5, or4-((Methyl-1-piperazinyl)methyl)-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamidemethanesulfonate, has been registered in many countries as anticancerdrug. This Gleevec™ compound (compound 53) is also the most active onein the indication prion diseases.

[0027] The name “prion” is used to describe the causative agents whichunderlie the transmissible spongiform encephalopathies. A prion isproposed to be a novel infectious particle that differs from viruses andviroids. It is composed solely of one unique protein that resists mostinactivation procedures such as heat, radiation, and proteases. Thelatter characteristic has led to the term protease-resistant isoform ofthe prion protein. The protease-resistant isoform has been proposed toslowly catalyze the conversion of the normal prion protein into theabnormal form.

[0028] The term “isoform” in the context of prions means two proteinswith exactly the same amino acid sequence that are folded into moleculeswith dramatically different tertiary structures. The normal cellularisoform of the prion protein (PrP^(c)) has a high α-helix content, a lowβ-sheet content, and is sensitive to protease digestion. The abnormal,disease-causing isoform (PrP^(Sc)) has a lower α-helix content, a muchhigher β-sheet content, and is much more resistant to proteasedigestion.

[0029] Moreover, in a more general sense, the present invention isconcerned with the prophylaxis ans/or treatment of neurodegenerativediseases. For example, Alzheimer is a well-known neurodegenerativedisease.

[0030] Preferred are the compounds wherein R represents hydrogen. Alsopreferred are compounds wherein Z represents —NH—CO—X or —NH—SO₂—Xand/or wherein Y, Y′, Y″ are independently of each other —H, —F, —Cl,CH₂F, —CH₂Cl, —OH, —OCH₃, —CN, —OCF₃, or a 4-methylpiperazin-1-yl-methylresidue.

[0031] Also preferred are the following pyridylpyrimidine derivativesselected from the group comprising:

[0032] Compound 1: (3-Nitrophenyl)4-pyridin-3-yl-pyrimidin-2-yl)-amine;

[0033] Compound 2:(3-Aminophenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine;

[0034] Compound 3:(5-Amino-2-methylphenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine;

[0035] Compound 4:4-Chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0036] Compound 5:4-Chloromethyl-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0037] Compound 6:4-(4-Methylpiperazin-1-ylmethyl)-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0038] Compound 7: Thiophene-3-carboxylic acid[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-pheny]-amide;

[0039] Compound 8:4-Chloro-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0040] Compound 9:4-Chloro-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0041] Compound 10:3,4,5-Trimethoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0042] Compound 11:4-Cyano-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0043] Compound 12:4-Methoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0044] Compound 13:4-Chloro-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0045] Compound 14: Thiophene-3-carboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0046] Compound 15:3,5-Dimethoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0047] Compound 16:3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0048] Compound 17:4-Cyano-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0049] Compound 18:4-Methoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0050] Compound 19:4-Chloro-N-[4-methyl-3-(4-pyridin-3-yl-pydmidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0051] Compound 20: Thiophene-3-carboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0052] Compound 21:3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0053] Compound 22:4-Trifluoromethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0054] Compound 23: Cyclohexanecarboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0055] Compound 24: Cyclohexanecarboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0056] Compound 25: Isoquinoline-5-sulfonic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0057] Compound 26: Isoquinoline-5-sulfonic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0058] Compound 27:(5-Nitro-2-methylphenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;

[0059] Compound 28:(5-Amino-2-methylphenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;

[0060] Compound 29:3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0061] Compound 30:4-Cyano-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0062] Compound 31:(3-Aminophenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;

[0063] Compound 32:4-Chloro-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0064] Compound 33: Cyclohexanecarboxylic acid[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0065] Compound 34:4-Cyano-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0066] Compound 35:4-Chloro-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0067] Compound 36:4-Methoxy-N-[4-methyl-3-(4-pyridin4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0068] Compound 37:4-Chloro-N-[4-methyl-3-(4-pyridin4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0069] Compound 38: Cyclohexanecarboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0070] Compound 39:3,5-Dimethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0071] Compound 40:(5-Amino-2-methylphenyl)-(4-pyridin-4-yl-pyrimidin-2-yl)-amine;

[0072] Compound 41: Thiophene-3-carboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0073] Compound 42:4-Chloro-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0074] Compound 43:4-Chloro-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0075] Compound 44:(3-Aminophenyl)-(4-pyridin-4-yl-pyrimidin-2-yl)-amine;

[0076] Compound 45:(3-Nitrophenyl)-(4-pyridin-4-yl-pyrimidin-2-yl)-amine;

[0077] Compound 46:4-Trifluoromethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0078] Compound 47: Isoquinoline-5-sulfonic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0079] Compound 48:4-Methoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0080] Compound 49:4Cyano-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0081] Compound 50:3,4,5-Trimethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0082] Compound 51:3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0083] Compound 52:3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0084] Compound 53:4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(Gleevec™);

[0085] Compound 54:4-Methyl-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide

[0086] Compound 55:4-Methoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0087] Compound 56:3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0088] Compound 57: Naphthalene-2-carboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0089] Compound 58:N-[3-(4-Pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0090] Compound 59:4-Chloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0091] Compound 60:4-Methoxy-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0092] Compound 61:4-Chloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0093] Compound 62: Thiophene-2-carboxylic acid3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;

[0094] Compound 63: Naphthalene-2-sulfonic-acid[3-(4-pyridin-2-yl-pydimidin-2-yl-amino)-phenyl]-amide;

[0095] Compound 64: Isoquinoline-5-sulfonic-acid[3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;

[0096] Compound 65: Cylopentanecarboxylic acid3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;

[0097] Compound 66: Naphthalene-2carboxylic acid[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0098] Compound 67:4-Cyano-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0099] Compound 68:3,5-Dimethoxy-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0100] Compound 69:4-Bromo-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0101] Compound 70:4-Methyl-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0102] Compound 71:4-Fluoro-N-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;

[0103] Compound 72:3,5-Dichloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0104] Compound 73:N-[3-(4-Pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0105] Compound 74:4-Chloromethyl-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0106] Compound 75:4-Methyl-N-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide

[0107] Compound 76:4-(4-Methylpiperazin-1-ylmethyl)-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0108] Compound 77: Naphthalene-2-carboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0109] Compound 78:2-Methoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0110] Compound 79:2-Methoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0111] Compound 80:4-Methyl-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0112] Compound 81:4-Methyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0113] Compound 82:N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0114] Compound 83:1(3,5-Diacetyl-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny]-urea;

[0115] Compound 84:1-{3,5-Bis-(amidinohydrazone)-phenyl}-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-urea;

[0116] Compound 85:N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-nicotinamide;

[0117] Compound 86:N-[3-(4-Pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-nicotinamide;

[0118] Compound 87: [1,8]Naphthyridine-2carboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0119] Compound 88: [1,8]Naphthyridine-2carbothioic acid[3-(4-pyridin-3yl-pyrimidin-2-ylamino)-phenyl]-amide;

[0120] Compound 89:2-Methoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0121] Compound 90:4-Trifluoromethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0122] Compound 91:4-Methyl-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;

[0123] and pharmaceutically active salts of these compounds.

[0124] Recent research has revealed how cells communicate with eachother to coordinate the growth and maintenance of the multitude oftissues within the human body. A key element of this communicationnetwork is the transmission of a signal from the exterior of a cell toits nucleus, which results in the activation or suppression of specificgenes. This process is called signal transduction.

[0125] An integral part of signal transduction is the interaction ofligands, their receptors and intracellular signal transductionmolecules. Ligands are messengers that bind to specific receptors on thesurface of target cells. As a result of the binding, the receptorstrigger the activation of a cascade of downstream signaling molecules,thereby transmitting the message from the exterior of the cell to itsnucleus. When the message reaches the nucleus, it initiates themodulation of specific genes, resulting in the production of RNA andfinally proteins that carry out a specific biological function.Disturbed activity of signal transduction molecules may lead to themalfunctioning of cells and disease processes. Specifically,interference of the pathogenic PrP^(Sc) from prion diseases withneuronal cells is necessary for the prion protein to induce itsneuropathological features such as neuronal vacuolization, neuronaldeath and gliosis with hyperastrocytosis.

[0126] A key element of this communication network is the transmissionof a signal from the exterior of a cell to its nucleus, which results inthe activation or suppression of specific genes. The human cellularprotein kinases Abl and clk1 are two of the enzymes involved in saidsignal transduction process. As revealed herein said kinases Abl andclk1 serve as targets and are inhibited by the pyridylpyrimidinecompounds of the general formula (I). It could be proved that prioninfections and/or prion diseases can be treated and also be prevented bythe inhibition of said kinase Abl using the inventive pyridylpyrimidinederivatives. Inhibition of the kinase clk1 by said pyridylpyrimidinecompounds can be used for the treatment of infections and diseases.

[0127] A microarray platform technology consisting of more than 1100signal transduction cDNAs has been established. The technology is usedfor the identification of changes in RNA expression patterns as a resultof the manipulation of the host cell by PrP^(Sc). In addition,differential display techniques were used in order to pinpoint thesechanges to those enzymes which could be potential targets for drugintervention.

[0128] Employing this predefined set of signal transduction relevantcDNAs on the filters, the expression pattern of signal transductionmRNAs in neuronal mouse cells transfected with the pathogenic form ofthe prion protein (PrP^(Sc)) were compared with the same cellstransfected with the non-pathogenic wild-type form (PrP^(c)) as acontrol. Interference of the PrP^(Sc) with the cellular signaling eventsis reflected in different gene expression when compared to the controlcellular situation (PrP^(c)).

[0129] Using this technology, the human cellular protein kinases FGF-R1(also known as fIg, FI-1, FIt-2, or b-FGFR), Tkt (also known as CCK-2,DDR-2, or EDDR, EC Number 2.7.1.112), Abl (also known as c-abl), clk1,MKK7 (also known as SKK4, SAPKK4, SAPKK5, or JNKK2), LIMK-2, CaM-KI,JNK2 (also known as SAPK1a, SAPKalpha), CDC2 (also known as CDK1), PRK,the human cellular protein phosphatases PTP-SL (also known as MCP83),PTP-zeta, the cellular signal transduction molecules HSP86, and GPIR-1were identified as potential anti-prion disease targets. Said cellularprotein kinases, phosphatases and signal transduction molecules arefound to be specifically up- or downregulated by PrP^(Sc) in relevantmouse neuronal cells.

[0130] Surprisingly, it was found that the following human cellulartargets are significantly up- or downregulated in prion infected cells:target regulation FGF-R1 3.6 fold stronger Abl 5.6 fold stronger MKK74.1 fold stronger CDC2 2.0 fold weaker Tkt 2.1 fold stronger LIMK-2 2.1fold stronger CaM-KI 2.1 fold stronger JNK2 2.0 fold weaker PRK 2.0 foldweaker PTPzeta 4.6 fold weaker PTP-SL 5.0 fold weaker HSP86 4.1 foldweaker GPIR-1 2.3 fold weaker

[0131] Thus, one aspect of the present invention relates to a method forpreventing and/or treating prion infections and/or diseases associatedwith said prion infections in an individual which comprisesadministering to the individual an amount of at least one compound ofthe general formula (I) and/or pharmaceutically acceptable salts thereofeffective to prevent and/or treat said prion infections and/or priondiseases. Most preferred is the administration of a compound accordingto claim 8.

[0132] It could be proven that inhibition of one target selected fromFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1 was effective to treat prion diseases.Therefore, another aspect of the invention relates to a method forpreventing and/or treating prion infections and/or prion diseases in anindividual comprising the step of administering a pharmaceuticallyeffective amount of at least one compound according of the generalformula (I) and/or pharmaceutically acceptable salts thereof whichinhibits at least partially the activity of one target selectef fromFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1.

[0133] The nucleoside sequences of the genes coding for the humancellular protein kinase Abl and the protein kinase clk1 and their aminoacid sequences are disclosed in form of a sequence listing shown below.The nucleoside and amino acid sequences for the kinase Abl (AccessionNumber: M14752) and for the kinase clk1 (Accession Numbers: XM002520,NM004071, L29222, L29219) were obtained from NCBI (National Library ofMedicine: PubMed).

[0134] The compounds of general formula (I) were identified asinhibitors of at least one target selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1 by the use of a method for detecting compoundsuseful for the prophylaxis and/or treatment of prion infections and/ordiseases. Said method comprises

[0135] a) contacting a test compound with at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1; and

[0136] b) detecting the activity of said human cellular protein kinase,phosphatase or cellular signal transduction molecule.

[0137] The activity of a human cellular protein kinase, phosphatase orcellular signal transduction molecule was preferably measured by meansof an enzymatic assay.

[0138] As used herein, the term “inhibitor” refers to any compoundcapable of downregulating, decreasing, suppressing or otherwiseregulating the amount and/or activity of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1. Generally,said inhibitors, including suicide inhibitors, may be proteins, oligo-and polypeptides, nucleic acids, genes, small chemical molecules, orother chemical moieties.

[0139] The present disclosure teaches for the first time the up- ordownregulation of the above-mentioned human cellular protein kinases,phosphatases, or cellular signal transduction molecules specificallyinvolved in prion infections and/or diseases. Thus, the presentinvention is also directed to a method for detecting prion infectionsand/or diseases in an individual comprising:

[0140] a) providing a sample from said individual; and

[0141] b) adding to said sample a pharmaceutically effective amount ofat least one pharmaceutically active agent; and

[0142] c) detecting activity in said sample of at least one humancellular protein kinase, phosphatase or cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.

[0143] As used herein the term “sample” refers to any sample that can betaken from a living animal or human for diagnostic purposes, especiallysaid sample comprises blood, milk, saliva, sputum, excrement, urine,spinal cord liquid, liquor, lachrymal gland liquid, biopsies and allother samples that can be taken from a living animal or human fordiagnostic purposes.

[0144] The term “individual” preferably refers to mammals, especiallyhumans or ruminants. Ruminants are, for instance, muledeer, elk, cow,cattle, sheep, goat, deer, or buffalo. Minks are an example for mammalswhich do not belong to the species of ruminants.

[0145] As used herein the term “ruminants” refers to an animal, forinstance, cattle, sheep, goat, deer, elk, or buffalo that has fourseparate stomach chambers, and is therefore able to digest a wide rangeof organic and plant foods. The term “ruminants” refers also to exoticruminants, like captive nyala, gemsbok, Arabian oryx, eland, kudu,scimitar-horned oryx, ankole, or bison which are also accessible todevelop spongiform encephalopathy.

[0146] A similar aspect of the present invention is directed to a methodfor detecting prion infections and/or prion diseases in cells, cellcultures and/or cell lysates comprising:

[0147] a) providing said cells, cell cultures and/or cell lysates; and

[0148] b) adding to said cells, cell cultures and/or cell lysates apharmaceutically effective amount of at least one pharmaceuticallyactive agent; and

[0149] c) detecting activity in said sample of at least one humancellular protein kinase, phosphatase or cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.

[0150] Furthermore, it has been shown that the inhibition of at leastone target selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1has an effect on the production of prions. Therefore, another aspect ofthe invention relates to a method for regulating the production ofprions in an individual or in cells comprising the step of administeringa pharmaceutically effective amount of at least one pharmaceuticallyactive agent which inhibits at least partially the activity of at leastone human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, GPIR-1, or which inhibits at least partially the production of atleast one human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, GPIR-1.

[0151] The inventive compounds according to general formula (I) areexamples for the above-mentioned pharmaceutically active agent.Preferably the targets FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, andCDC 2 are used with said methods.

[0152] Another type of pharmaceutically active agents useful within themethods disclosed herein are monoclonal or polyclonal antibodies whichbind to a human cellular protein kinase, phosphatase or a cellularsignal transduction molecule selected from the group comprising FGF-R1,Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1. Thus, a further aspect of the present invention isrelated to said monoclonal or polyclonal antibodies which bind to ahuman cellular protein kinase, phosphatase or a cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1.

[0153] Another embodiment of the present invention utilizes thescientific findings that some targets such as JNK2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1 are downregulated during prion infection andthat upregulation of the effected target by means of an activator leadsto an alternative way of treating prion infections and diseasesassociated with prion infection.

[0154] Thus, a method was developed for regulating the production ofprions either in an individual or in cells. Said methods comprise thestep of administering an individual or the cells a pharmaceuticallyeffective amount of at least one pharmaceutically active agent whereinsaid agent activates at least partially the activity of at least onehuman cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1, or wherein said agent at least partially activates orstimulates the production of at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1 .

[0155] Preferably the targets JNK2, PRK, PTP-SL, PTP-zeta, HSP86, andGPIR-1 are used within the above-described methods.

[0156] Because of the fact that the organism may upregulate a giventarget such as FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, and CDC 2in order to compete with the prion infection, it is also a reasonableapproach to further support said upregulation by means of an activator.Therefore, the above-mentioned methods apply either to targets which aredownregulated but also to targets which are upregulated.

[0157] The novel and partially known pyridylpyrimidine compounds of thegeneral formula (I) represent a new class of pharmaceuticals highlyuseful for the prophylaxis and treatment of prion infections and priondiseases.

[0158] Thus, a further aspect of the present invention describes the useof a compound of the general formula (I) and/or pharmaceuticallyacceptable salts thereof for the manufacture of a pharmaceuticalformulation for prophylaxis and/or treatment of prion infections and/ordiseases induced or caused by prion infection.

[0159] As used herein the Term “prion diseases” refers to transmissiblespongiform encephalopathies. This group of neurologic diseases affectshumans and many species of animals causing a “sponge-like” degenerationof brain tissue. Among other unique features, all of these diseases areassociated with the accumulation of an abnormal form of the prionprotein in nerve cells that eventually leads to the death of the host.While prion diseases can all be transmitted from one host to another, itremains contentious as to whether a virus-like infectious agent or theabnormal prion protein itself, the prion, causes the conversion ofnormal to abnormal protein.

[0160] Probably most mammalian species develop prion diseases. Specificexamples for animals include: Scrapie sheep, goat TME (transmissiblemink encephalopathy): mink CWD (chronic wasting disease): muledeer,deer, elk BSE (bovine spongiform encephalopathy): cows, cattles

[0161] Humans are also susceptible to several prion diseases. Examplesare: CJD Creutzfeld-Jacob Disease GSS Gerstmann-Sträussler-Scheinkersyndrome FFI Fatal familial Insomnia Kuru Alpers Syndrome

[0162] The human prion diseases include kuru, sporadic Creutzfeldt-Jakobdisease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD),Gerstmann-Sträussler-Scheinker (GSS) disease, fatal familial insomnia(FFI), and, more recently, new variant CJD (nvCJD or vCJD). In additionto these human diseases, prion-related diseases, have been recognized inseveral animal hosts. Scrapie is a naturally occurring disease of sheepand goats that causes ataxia, behavioral changes, and a severe pruritusthat leads to scraping behavior, from which the disease was named.Additional prion diseases in animals include transmissible minkencephalopathy (TME), chronic wasting disease (CWD) of deer and elk,feline spongiform encephalopathy (FSE), and bovine spongiformencephalopathy (BSE), among others.

[0163] The transmissible nature of prion disease was first demonstratedexperimentally in 1936 when Cuillé and Chelle transmitted scrapie to ahealthy goat by the intraocular administration of scrapie-infectedspinal cord. Thirty years later, sCJD was transmitted to chimpanzees.The pathologic feature common to all these diseases is a prominentvacuolation of the gray matter of the brain that produces a“sponge-like” appearance on light microscopy. This histopathologicappearance, coupled with the transmissible nature of these diseases, ledto their collective designation as “transmissible spongiformencephalopathies” or TSEs.

[0164] The etiologic agent of the TSEs was proposed to be a “slow virus”to explain its transmissible nature and the prolonged incubation periodobserved during experimental transmission studies. Early experimentssuggested that protein may be a critical component of the infectiousagent. These studies established the basis for a new form of atransmissible pathogen, one that is composed ostensibly of only proteinand lacks any replicative elements such as nucleic acid.

[0165] The term “prion” was coined to indicate an infectious agent withproteinlike properties. The unusual properties of the pathogen weredemonstrated in early experiments in which conditions that degradenucleic acids, such as exposure to ionizing and ultraviolet radiation,did not reduce the infectivity of scrapie fractions. On the other hand,treatments that degrade protein, such as prolonged exposure toproteases, correlated with a reduction in infectivity. A protein withrelative resistance to protease digestion was found to be consistentlypresent in the brains of animals and humans with TSE. Surprisingly, thisprotein was found to be one that is normally encoded by a chromosomalgene of the host.

[0166] Thus, the question raised, how a normally expressed protein couldalso be a transmissible pathogen? It was hypothesized and laterdemonstrated that PrP exists in two major isoforms: the nonpathogenic orcellular form, designated PrP^(c), and the pathogenic orscrapie-inducing form, designated PrP^(Sc). Both PrP^(c) and PrP^(Sc)have the same amino acid sequence, yet they differ in their biochemicalproperties: PrP^(c) is soluble in nondenaturing detergents andcompletely degraded by proteases, whereas PrP^(Sc) is insoluble innondenaturing detergents and shows a relative resistance to proteases.Structural studies of PrP^(c) and PrP^(Sc) indicate a difference in theconformation of the two isoforms: PrP^(c) is predominantly helical,whereas PrP^(Sc) contains at least 40% pleated sheet structure.Conversion to this sheet structure appears to be the fundamental eventin prion disease. The ultimate mechanism of how cells die coincidentwith the generation of prions is still unclear. Simple accumulation ofpathogenic protein may not be sufficient to explain disease, however, itmay constitute a critical step in cellular dysfunction.

[0167] It was shown that the pyridylpyrimidine compounds of the generalformula (I) are highly effective for the prophylaxis and/or treatment ofprion infections and/or prion diseases selected from the groupcomprising Scrapie, TME, CWD, BSE, CJD, vCJD, GSS, FFI, Kuru, and AlpersSyndrome. Preferably, the pyridylpyrimidine derivatives are used forpreventing and/or treating BSE, vCJD, or CJD.

[0168] The above-mentioned prion infections and/or diseases associatedwith prion infections can be treated using the inventivepyridylpyrimidine derivatives by targeting at least one of the humancellular protein kinases, phosphatases or cellular signal transductionmolecules selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.Thereby, the compounds according to general formula (I) act asinhibitors for at least one of the above-mentioned targets andespecially as inhibitors for at least one enzyme selected from the groupcomprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, and CDC 2.

[0169] According to these findings a further aspect of the presentinvention is directed to a method for preventing and/or treating prioninfections and/or prion diseases in an individual comprising the step ofadministering a pharmaceutically effective amount of at least onepharmaceutically active agent which inhibits at least partially theactivity of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1, or which inhibits at least partially theproduction of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1.

[0170] Another aspect is related to a method for preventing and/ortreating prion infections and/or prion diseases in cells or cellcultures comprising the step of administering a pharmaceuticallyeffective amount of at least one pharmaceutically active agent whichinhibits at least partially the activity of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1, or whichinhibits at least partially the production of at least one humancellular protein kinase, phosphatase or cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.

[0171] The inventive pyridylpyrimidine compounds of formula (I) areexamples for the above-mentioned inhibitor. Said pyridylpyrimidinecompounds and/or pharmaceutically acceptable salts thereof areadministered in a dosage corresponding to an effective concentration inthe range of 0.01-50 μM, preferably in the range of 0.01-10 μM, morepreferably in the range of 0.01-1 μM, and most preferably in the rangeof 0.01-0.1 μM.

[0172] Because of the fact that the targets JNK2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1 are downregulated in cells infected with prions, anupregulation of said targets represents another strategy in order totreat prion infections and diseases like CJD (nvCJD or vCJD) associatedwith prion infections. Said upregulation can be performed by activators.

[0173] An agent that is able to upregulate, increase, activate, orstimulate the activity of at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1, but especially of JNK2,PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1 is named “activator”.

[0174] Thus, another embodiment of the present invention describes amethod for preventing and/or treating prion infections and/or diseasesin an individual comprising the step of administering a pharmaceuticallyeffective amount of at least one pharmaceutically active agent whichactivates at least partially the activity of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1, or whichactivates or stimulates the production of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.Preferably, said method is directed to the targets JNK2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1.

[0175] As used herein, the term “agent” or “pharmaceutically activeagent” refers to any chemical compound capable of down- or upregulating,de- or increasing, suppressing, activation, stimulating or otherwiseregulating the amount and/or activity of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1. Generally,said agents may be proteins, oligo- and polypeptides, nucleic acids,genes, aptamers, small chemical molecules, or other chemical moieties.An agent may be either an inhibitor or an activator and especially aninhibitor for the enzymes FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,and CDC 2 and an activator for the targets JNK2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1.

[0176] One special kind of said pharmaceutically active agents areaptamers which function as regulators of the activity of a wide range ofcellular molecules such as human cellular protein kinase andphosphatase. Aptamers are nucleic acid molecules selected in vitro tobind small molecules, peptides, or proteins with high affinity andspecificity. Aptamers not only exhibit highly specific molecularrecognition properties but are also able to modulate the function oftheir cognate targets in a highly specific manner by agonistic orantagonistic mechanisms. Most famous examples for aptamers are DNAaptamers or RNA aptamers.

[0177] Further examples for pharmaceutically active agents are thepyridylpyrimidine compounds of the present invention and/orpharmaceutically acceptable salts thereof. Said compounds areadministered in a dosage corresponding to an effective concentration inthe range of 0.01-50 μM, preferably in the range of 0.01-10 μM, morepreferably in the range of 0.01-1 μM, and most preferably in the rangeof 0.01-0.1 μM.

[0178] The compounds of general formula (I) can be administered in adaily dosage in the range of 25 mg to 1000 mg, preferably in a dailydosage of 400 mg to 600 mg, more preferably in a daily dosage of 500 mg,and most preferably in continuously increased daily dosages starting ata initial daily dosage of 400 mg and ending up in a daily dosage of 600mg at the end of the treatment.

[0179] A question is how PrP^(c) does convert to PrP^(Sc)? Potentialmechanisms that initiate conversion of PrP^(c) to PrP^(Sc) include agerm line mutation of the human prion protein gene (PRNP), a somaticmutation within a particular neuron, and spontaneous conversion ofPrP^(c) to an aberrant conformation that is not refolded appropriatelyto its native structure. The prion protein gene (PRNP) is the singlegene on the short arm of chromosome 20 in humans which encodes thenormal cellular isoform of the prion protein. Regardless of theinitiating event, once an “infectious unit” has been generated, PrP^(Sc)appears to act as a conformational template by which PrP^(c) isconverted to a new molecule of PrP^(Sc) through protein-proteininteraction of PrP^(Sc) and PrP^(c). This concept is supported byseveral studies which show that mice with the normal PrP gene deleted(PrP knockout mice) do not develop prion disease after inoculation withscrapie. Furthermore, transgenic (Tg) mice that express a chimeric PrPgene made of human and mouse segments develop protease-resistantchimeric mouse-human Prp^(Sc) in their brains when inoculated with brainextracts from humans with prion disease. These findings clearlyillustrate that prions do not self-replicate but instead convertnonpathogenic PrP^(c) to pathogenic PrP^(Sc).

[0180] In its sporadic or nonfamilial form, CJD is the most common ofthe human prion diseases. Confusion and forgetfulness which progressrapidly to severe cortical dementia in combination with ataxia,myoclonus, and an abnormal electroencephalogram (EEG) represents the“classic tetrad” of CJD. However, a host of other neurologic signs andsymptoms, including diffuse or focal weakness, painful neuropathy,chore-iform movements, hallucinations, cortical blindness, primarylanguage disturbance, supranuclear ophthalmoplegia, and alien handsyndrome, among others, have been observed. As the disease progressesfrom the early stage, ataxia commonly limits the patient's mobility.

[0181] Familial CJD (fCJD) includes those cases with a dominantlyinherited mutation of the PRNP gene, in which the pathologic features ofspongiform change occur in the absence of GSS-type plaques. Although,familial cases of CJD tend to have a clinical and pathologic phenotypesimilar to that of sCJD.

[0182] The original description of a patient with the onset of ataxiaand dysarthria followed by variable degrees of pyramidal andextrapyramidal symptoms and late developing dementia defines the classicpresentation of GSS. The duration of said disease ranges from 2 to 10years. Death usually results from secondary infection, often fromaspiration pneumonia because of impaired swallowing. The presence ofplaque deposits regionally or diffusely throughout the cortex that areimmunoreactive to anti-human PrP antibodies is the hallmark of this formof prion disease.

[0183] FFI is a genetic disorder which manifests itself by many symptomsdue to the degeneration of a certain part of the brain, the thalamus.The affected area of the brain is the area responsible for sleep, thethalamus. The thalamus is the center which communications from the brainto the body and the body to the brain pass through for proper directionsto where a signal should be received. When sleep takes place, it isthought that the thalamus becomes less efficient at this signal transferfunction allowing for the vegetative state of sleep to come over anindividual. Consequently, the symptoms of fatal familial insomnia aredirectly related to the malfunction of the responsibilities of thethalamus, namely sleep.

[0184] There are four stages of the disease before an individual's lifeends. The first stage is progressive insomnia, the characteristicfeature of fatal familial insomnia. By now, there is no cure for thisillness.

[0185] The term “familial” means: affecting several members of the samefamily, usually as a result of an underlylng genetic mutation.

[0186] The occurrence of vCJD is sobering because it appears torepresent a situation in which the prion has “jumped” species, in thiscase from cow to human. Because the pathologic features and clinicalpresentation of vCJD differ significantly from those of sCJD, it isconsidered a new “strain” of human prion disease. The same “proteinsignature” was observed following experimental transmission of BSE toseveral animal hosts, supporting the idea that vCJD results from theinfection of humans with BSE. vCJD occurs primarily in youngerindividuals (average age 27) with a somewhat protracted course ofapproximately 16 months. The brain shows diffuse vacuolation and thepresence of distinctive dense core PrP-containing plaques surrounded bya halo of spongiform change.

[0187] Kuru is the condition which first brought prion diseases toprominence in the 1950s. The disease was found in geographicallyisolated tribes in New Guinea. It was established that ingesting braintissue of dead relatives for religious reasons was likely to be theroute of transmission.

[0188] Alpers Syndrome is the name given to prion diseases in infants.

[0189] Scrapie is the accepted, albeit somewhat colloquial, name for thenaturally occurring transmissible spongiform encephalopathy of sheep andgoats found worldwide. Scrapie also infects laboratory mice and hamstersmaking it one of the most important sources of new scientificinformation about this group of disorders. Scrapie was the first exampleof this type of disease to be noticed and has been known about for manyhundreds of years. There are two possible methods of transmission insheep: a) Infection of pasture with placental tissue carrying the agentfollowed by ingestion, or b) direct sheep-lamb transmission. CWD is afatal neurodegenerative disease of deer and elk, now known to be atransmissible spongiform encephalopathy. To date, affected animals havebeen found exclusively in the United States.

[0190] BSE

[0191] Bovine spongiform encephalopathy or “mad cow disease” appears tohave originated from scrapie that has been recognized in Europe sincethe mid-18th century. It has since spread to most sheep-breedingcountries and is widespread in the United Kingdom, where until 1988 therendered carcasses of livestock (including sheep) were fed to ruminantsand other animals as a protein-rich nutritional supplement.

[0192] During rendering, carcasses from which all consumable parts hadbeen removed were milled and then decomposed in large vats by boiling atatmospheric or higher pressures, producing an aqueous slurry of proteinunder a layer of fat (tallow). After the fat was removed, the slurry wasdesiccated into a meat and bone meal product that was packaged by theanimal food industry and distributed to owners of livestock and othercaptive animals (e.g., zoo and laboratory animals, breeding species,pets).

[0193] A further aspect is related to a method for regulating theexpression of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1 in an individual comprising the step ofadministering the individual a pharmaceutically effective amount of atleast one pharmaceutically active agent wherein said agent inhibits atleast partially the transcription of DNA or the translation of RNA.

[0194] And a still further aspect of the present invention relates to amethod for regulating the expression of at least one human cellularprotein kinase, phosphatase or cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1 in thecells, the method comprising the step of administering the cells apharmaceutically effective amount of at least one pharmaceuticallyactive agent wherein said agent inhibits at least partially thetranscription of DNA or the translation of RNA.

[0195] As used herein, the term “regulating expression and/or activity”generally refers to any process that functions to control or modulatethe quantity or activity (functionality) of a cellular component. Staticregulation maintains expression and/or activity at some given level.Upregulation refers to a relative increase in expression and/oractivity. Accordingly downregulation refers to a relative decrease inexpression and/or activity. Downregulation is synonymous with inhibitionof a given cellular component's activity.

[0196] The transcription of DNA and the translation of RNA can beinhibited by oligonucleotides or oligonucleotide derivatives. Thus, thepresent invention discloses oligonucleotides and derivatives ofoligonucleotides which may be used in the above-mentioned methods. Theoligonucleotide and/or its derivatives bind to the DNA and/or RNAencoding a human cellular protein kinase, phosphatase or a cellularsignal transduction molecule selected from the group comprising FGF-R1,Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1 and suppress the transcription of DNA or translationof RNA.

[0197] As described above, said prion infection and/or diseaseassociated with said prion infection is selected from the groupcomprising Scrapie, TME, CWD, BSE, vCJD, CJD, GSS, FFI, Kuru, and AlpersSyndrome. Preferably, the method is used for prophylaxis and/ortreatment of BSE, vCJD, or CJD. The above disclosed methods arepreferably applied to CJD, vCJD, and BSE, more preferably applied tovCJD and BSE, and most perferably applied to BSE.

[0198] Some methods of the present invention identify compounds usefulfor prophylaxis and/or treatment of prion infections and/or diseases byscreening a test compound, or a library of test compounds; for itsability to inhibit at least one of the above-mentioned human cellularprotein kinases, phosphatases, or cellular signal transductionmolecules, identified herein as characteristically up- or downregulatedduring prion production or growth inside a cell or individual. A varietyof assay protocols and detection techniques are well known in the artand easily adapted for this purpose by a skilled practitioner. Suchmethods include, but are not limited to, high throughput assays (e.g.,microarray technology, phage display technology), and in vitro and invivo cellular and tissue assays.

[0199] Thus, a solid support is disclosed in the present inventionuseful for screening compounds useful for the prophylaxis and/ortreatment of prion infections and/or diseases in an individual, thesolid support comprising at least one immobilized oligonucleotide,wherein said oligonucleotide encodes one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.

[0200] A further aspect of the present invention is related to a solidsupport useful for screening compounds useful for the prophylaxis and/ortreatment of prion infections and/or diseases in an individual, thesolid support comprising at least one immobilized human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.

[0201] In another embodiment, a component of the above-mentioned methodscomprises peptide fragments of one or more of the above-identified humancellular protein kinases, phosphatases or cellular signal transductionmolecules immobilized on a solid support. Once again the most preferredsolid support embodiment would contain polymers of sufficient qualityand quantity to detect all of the above-mentioned human cellular proteinkinases, phosphatase and cellular signal transduction molecules (e.g., anucleic acid or a peptide microarray). A variety of supports andconstructions of the same for the methods disclosed herein are wellknown in the art and easily adapted for this purpose by a skilledpractitioner (cf., for example: Marschall, 1999 “Do-it-yourself genewatching” Science 286, 444-447; Service 2000 “Protein arrays step out ofDNA's shadow” Science 289, 1673).

[0202] It is preferred that mRNA is measured as an indication ofexpression. Methods for assaying for mRNA include, but are not limitedto, Northern blots, slot blots, dot blots, and hybridization to anordered array of oligonucleotides. Nucleic acid probes useful for assayof a sample are preferably of sufficient length to specificallyhybridize only to appropriate, complementary transcripts. Typically theoligonucleotide probes will be at least 10 to 25 nucleotides in length.In some cases longer probes of at least 30 to 50 nucleotides will bedesirable.

[0203] The cDNA oligonucleotides immobilized on said membrane filterwhich are used for detecting the up- or downregulation of theabove-mentioned human cellular protein kinases, phosphatases, andcellular signal transduction molecules by hybridization to theradioactively labeled cDNA probes have the nucleotide sequences listedin table 1. TABLE 1 Nucleotide sequences of cDNA-arrays Sequence ofimmobilized DNA Cellular kinase, phosphatase, or on arrays (in relationto the signal transduction molecule respective Acc No) FGF-R1 41 bp-2619bp (X52833) Tkt (EC 2.7.1.112) 1 bp-3096 bp (X74764) Abl 2153 bp-3765 bp(M14752) clk1 156 bp-1610 bp (L29219) MKK7 77 bp-1323 bp (AF013588) CDC277 bp-1050 bp (X05360) CaMKI 145 bp-1452 bp (L41816) JNK2 507 bp-1782 bp(L31951) LIMK-2 963 bp-2047 bp (D45906) PRK n.a bp-1862 bp (U56998) PTPzeta (EC 3.1.3.48) 148 bp-7604 bp (X54135) PTP-SL 862 bp-1902 bp(NM_002849) HSP86 n.a bp—n.a bp (X07270) GPIR-1 n.a bp—n.a bp (n.a)

[0204] Tkt has been assigned to the EC Number: 2.7.1.112

[0205] PTP zeta has been assigned to the EC Number: 3.1.3.48

[0206] The nucleoside sequences of the genes coding for the humancellular protein kinases, phosphatases, or cellular signal transductionmolecules listed in Table 1 together with the amino acid sequences andthe enzyme commission numbers (E.C. numbers) of said enzymes can beobtained from NCBI (National Library of Medicine: PubMed; Web address:www.ncbi.nlm.nih.gov/entrez).

[0207] The polypeptide product of gene expression may be assayed todetermine the amount of expression as well. Methods for assaying for aprotein include, but are not limited to, western blot,immuno-precipitation, radioimmuno assay, and peptide immobilization inan ordered array. It is understood, however, that any method forspecifically and quantitatively measuring a specific protein or mRNAproduct can be used.

[0208] A variety of supports upon which nucleic acids or peptides can beimmobilized are known in the art, for example filters, or polyvinylchloride dishes. Any solid surface to which oligonucleotides or peptidescan be bound, either directly or indirectly, either covalently ornon-covalently, can be used. A preferred solid support is a microarraymembrane filter or a “biochip”. These contain particular polymer probesin predetermined locations on the array. Each predetermined location maycontain more than one molecule of the probe, but each molecule withinthe predetermined location has an identical sequence.

[0209] The present invention incorporates by reference in their entiretytechniques well known in the field of molecular biology. Thesetechniques include, but are not limited to, techniques described in thefollowing publications:

[0210] Ausubel, F. M. et al. eds., “Short Protocols In MolecularBiology” 4^(th) Ed. 1999, John Wiley & Sons, NY (ISBN 0-471-32938-X);

[0211] Old, R. W. & S. B. Primrose “Principles of Gene Manipulation: AnIntroduction To Genetic Engineering” 3^(rd) Ed. 1985, BlackwellScientific Publications, Boston. Studies in Microbiology: V.2, 409 pp.(ISBN 0-632-01318-4);

[0212] Mayer, R. J. & J. H. Walker eds. “Immunochemical Methods In Celland Molecular Biology” 1987, Academic Press, London. 325 pp. (ISBN0-12480-855-7);

[0213] Winnacker, E. L. “From Genes To Clones: Introduction To GeneTechnology” 1987 VCH Publishers, NY. (translated by Horst Ibelgaufts)634 pp. (ISBN 0-89573-614-4).

[0214] As described above, a microarray platform technology wasdeveloped consisting of more than 1100 signal transduction cDNAsimmobilized on a solid support. Thus, another aspect of the presentinvention is directed to a solid support useful for detecting prioninfections and/or diseases in an individual, the solid supportcomprising an immobilized oligonucleotide, wherein said oligonucleotideis capable of detecting activity of at least one human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.

[0215] The present invention discloses also for the first time a solidsupport useful for detecting prion infections and/or diseases in cells,the solid support comprising an immobilized oligonucleotide, whereinsaid oligonucleotide is capable of detecting activity of at least onehuman cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1.

[0216] The present invention further incorporates by reference in theirentirety techniques well known in the field of microarray constructionand analysis. These techniques include, but are not limited to,techniques described in the following patents and patent applicationsdescribing array of biopolymeric compounds and methods for theirfabrication:

[0217] U.S. Pat. Nos. 5,807,522; 6,087,102; WO 93/17126; WO 95/11995; WO95/35505; EP 742 287; and EP 799 897.

[0218] Techniques also include, but are not limited to, techniquesdescribed in the following patents and patent application describingmethods of using arrays in various applications;

[0219] U.S. Pat. Nos. 5,994,076; 6,033,860; 6,040,138; 6,040,140; WO95/21265; WO 96/31622; WO 97/10365; WO 97/27317; EP 373 203; and EP 785280

[0220] Still a further aspect of the present invention is directed topharmaceutical compositions comprising at least one pharmaceuticallyactive agent together with a pharmaceutically acceptable carrier,excipient or diluents. Examples for pharmaceutically active agents arethe above-mentioned inventive compounds according to formula (I), orother small chemical molecules, antibodies, aptamers, oligo- andpolynucleotides, genes and other biological components capable ofregulating the activity of at least one target selected from the groupcomprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2,PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1, or which are effective totreat prion infections and diseases associated with prion infection.Said prion infections and diseases are preferably Scrapie, TME, CWD,BSE, vCJD, CJD, GSS, FFI, Kuru, and Alpers Syndrome.

[0221] Thus, the pharmaceutical compositions according to the presentinvention may comprise an inhibitor, such as the inventivepyridylpyrimidine compounds or an activator such as aptamers for atleast one target selected from FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1. It is alsopossible to have a combination of inhibitors or activators as activeingredients in one single pharmaceutical composition. Furthermore,suitable are also combinations of at least one inhibitor and at leastone activator for different targets within a single pharmaceuticalcomposition. For example, a pharmaceutical composition could comprisecompound 12 as an inhibitor for, for instance, the target Abl, and anactivator such as an aptamer for, for instance, the human cellularprotein kinase JNK2.

[0222] Said pharmaceutical compositions are useful for the prophylaxisand/or treatment of an individual afflicted with prions comprising atleast one agent capable of inhibiting and/or activating at leastpartially the activity, the expression, and/or the production of atleast one human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1.

[0223] The pyridylpyrimidine compounds of the present invention arebasic and form pharmaceutically acceptable salts with organic andinorganic acids. Examples of suitable acids for such acid addition saltformation are hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid,salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid,succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonicacid, perchloric acid, nitric acid, formic acid, propionic acid,gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvicacid, phenylacetic acid, benzoic acid, p-aminobenzoic acid,p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid,nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid,p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid,camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid,hydrogen-benzenesulfonic acid, picric acid, adipic acid,d-o-tolyltartaric acid, tartronic acid, α-toluic acid, (o, m, p)-toluicacid, naphthylamine sulfonic acid, and other mineral or carboxylic acidswell known to those skilled in the art. The salts are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce a salt in the conventional manner.

[0224] It is also possible to obtain acid addition salts with aminoacids like methionine, tryptophane, lysine or arginine, especially withpyridylpyrimidine compounds of the general formula (I) carrying acarboxylic acid residue.

[0225] Depending upon the substituents on the inventivepyridylpyrimidine compounds, one may be able to form salts with bases,too. Thus, for example, if there are carboxylic acid substituents in themolecule, salts may be formed with inorganic as well as organic basessuch as, for example, NaOH, KOH, NH₄OH, tetraalkylammonium hydroxide,and the like.

[0226] The compounds of the general formula (I) can also be administeredin form of their pharmaceutically active salts optionally usingsubstantially nontoxic pharmaceutically acceptable carriers, excipientsor diluents. The medications of the present invention are prepared in aconventional solid or liquid carrier or diluents and a conventionalpharmaceutically-made adjuvant at suitable dosage level in a known way.The preferred preparations are in administratable form which is suitablefor oral application. These administratable forms, for example, includepills, tablets, film tablets, coated tablets, capsules, powders anddeposits.

[0227] The preferred administratable forms are tablets, film tablets,coated tablets, gelatin capsules, and opaque capsules. Eachpharmaceutical composition contains at least one compound of the generalformula (I), preferably compound 53 and/or pharmaceutically acceptablesalts thereof in an amount of 50 mg to 150 mg, preferably 80 mg to 120mg, and most preferably in an amount of 100 mg per formulation.

[0228] Furthermore, the subject of the present invention also includespharmaceutical preparations for parenteral, including dermal,intradermal, intragastrical, intracutaneous, intravasal, intravenous,intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal,percutaneous, rectal, subcutaneous, sublingual, topical or transdermalapplication, which in addition to typical vehicles and diluents containa pyridylpyrimidine compound of the general formula (I) and/or apharmaceutically acceptable salt thereof as active ingredient.

[0229] Within the disclosed methods the pharmaceutical compositions ofthe present invention, containing pyridylpyrimidine derivatives of thegeneral formula (I) as active ingredients, will typically beadministered in admixture with suitable carrier materials selected withrespect to the intended form of administration, i.e. oral tablets,capsules (either solid-filled, semi-solid filled or liquid filled),powders for constitution, oral gels, elixirs, dispersible granules,syrups, suspensions, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of tablets or capsules, the active drug component may be combinedwith any oral nontoxic pharmaceutically acceptable inert carrier, suchas lactose, starch, sucrose, cellulose, magnesium stearate, dicalciumphosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms)and the like. Moreover, when desired or needed, suitable binders,lubricants, disintegrating agents and coloring agents may also beincorporated in the mixture. Powders and tablets may be comprised offrom about 5 to about 95 percent inventive composition.

[0230] Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among thelubricants, there may be mentioned for use in these dosage forms, boricacid, sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrants include starch, methylcellulose, guar gum and the like.Sweetening and flavoring agents and preservatives may also be includedwhere appropriate. Some of the terms noted above, namely disintegrants,diluents, lubricants, binders and the like, are discussed in more detailbelow.

[0231] Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize the therapeutic effects, i.e. antihistaminic activity and thelike. Suitable dosage forms for sustained release include layeredtablets containing layers of varying disintegration rates or controlledrelease polymeric matrices impregnated with the active components andshaped in tablet form or capsules containing such impregnated orencapsulated porous polymeric matrices.

[0232] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injections or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0233] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

[0234] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidifies.

[0235] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0236] The inventive pyridylpyrimidine compounds of the presentinvention may also be deliverable transdermally. The transdermalcompositions may take the form of creams, lotions, aerosols and/oremulsions and can be included in a transdermal patch of the matrix orreservoir type as are conventional in the art for this purpose.

[0237] The term capsule refers to a special container or enclosure madeof methyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

[0238] Tablet means compressed or molded solid dosage form containingthe active ingredients with suitable diluents. The tablet can beprepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation or by compaction well known to a personskilled in the art.

[0239] Oral gels refers to the active ingredients dispersed orsolubilized in a hydrophillic semi-solid matrix.

[0240] Powders for constitution refers to powder blends containing theactive ingredients and suitable diluents which can be suspended in wateror juices.

[0241] Suitable diluents are substances that usually make up the majorportion of the composition or dosage form. Suitable diluents includesugars such as lactose, sucrose, mannitol and sorbitol, starches derivedfrom wheat, corn rice and potato, and celluloses such asmicrocrystalline cellulose. The amount of diluents in the compositioncan range from about 5 to about 95% by weight of the total composition,preferably from about 25 to about 75%, more preferably from about 30 toabout 60% by weight.

[0242] The term disintegrants refers to materials added to thecomposition to help it break apart (disintegrate) and release themedicaments. Suitable disintegrants include starches, “cold watersoluble” modified starches such as sodium carboxymethyl starch, naturaland synthetic gums such as locust bean, karaya, guar, tragacanth andagar, cellulose derivatives such as methylcellulose and sodiumcarboxymethylcellulose, microcrystalline celluloses and cross-linkedmicrocrystalline celluloses such as sodium croscarmellose, alginatessuch as alginic acid and sodium alginate, clays such as bentonites, andeffervescent mixtures. The amount of disintegrant in the composition canrange from about 2 to about 20% by weight of the composition, morepreferably from about 5 to about 10% by weight.

[0243] Binders characterize substances that bind or “glue” powderstogether and make them cohesive by forming granules, thus serving as the“adhesive” in the formulation. Binders add cohesive strength alreadyavailable in the diluents or bulking agent. Suitable binders includesugars such as sucrose, starches derived from wheat, corn rice andpotato; natural gums such as acacia, gelatin and tragacanth; derivativesof seaweed such as alginic acid, sodium alginate and ammonium calciumalginate; cellulosic materials such as methylcellulose and sodiumcarboxymethylcellulose and hydroxypropylmethylcellulose;polyvinylpyrrolidone; and inorganics such as magnesium aluminumsilicate. The amount of binder in the composition can range from about 2to about 20% by weight of the composition, more preferably from about 3to about 10% by weight, even more preferably from about 3 to about 6% byweight.

[0244] Lubricant refers to a substance added to the dosage form toenable the tablet, granules, etc. after it has been compressed, torelease from the mold or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate or potassium stearate; stearic acid; high melting pointwaxes; and water soluble lubricants such as sodium chloride, sodiumbenzoate, sodium acetate, sodium oleate, polyethylene glycols andD,L-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present on the surfaces of the granulesand in between them and the parts of the tablet press. The amount oflubricant in the composition can range from about 0.2 to about 5% byweight of the composition, preferably from about 0.5 to about 2%, morepreferably from about 0.3 to about 1.5% by weight.

[0245] Glidents are materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

[0246] Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

[0247] As used herein, a “pharmaceutically effective amount” of aninhibitor and/or an activator is an amount effective to achieve thedesired physiological result, either in cells treated in vitro or in asubject treated in vivo. Specifically, a pharmaceutically effectiveamount is an amount sufficient to inhibit and or activate, for someperiod of time, one or more of the clinically defined pathologicalprocesses associated with the prion infection. The effective amount mayvary depending on the specific inhibitor and/or activator selected, andis also dependent on a variety of factors and conditions related to thesubject to be treated and the severity of the infection. For example, ifan inhibitor and/or activator is to be administered in vivo, factorssuch as the age, weight and health of the patient as well as doseresponse curves and toxicity data obtained in pre-clinical animal workwould be among those considered. If the inhibitor and/or activator is tobe contacted with the cells in vitro, one would also design a variety ofpre-clinical in vitro studies to assess such parameters as uptake,half-life, dose, toxicity, etc. The determination of a pharmaceuticallyeffective amount for a given pharmaceutically active agent is wellwithin the ability of those skilled in the art.

[0248] It is also apparent to a person skilled in the art that detectionincludes any method known in the art useful to indicate the presence,absence, or amount of a detection target. Such methods may include, butare not limited to, any molecular or cellular techniques, usedsingularly or in combination, including, but not limited to:hybridization and/or binding techniques, including blotting techniquesand immunoassays; labeling techniques (chemiluminescent, colorimetric,fluorescent, radioisotopic); spectroscopic techniques; separationstechnology, including precipitations, electrophoresis, chromatography,centrifugation, ultrafiltration, cell sorting; and enzymaticmanipulations (e.g., digestion).

[0249] It should be stressed that all above-mentioned features, aspects,and details of the present invention discussed and described inconnection with infections and infectious diseases, equally apply toneurodegenerative diseases, like Alzheimer.

[0250] It is readily apparent to those skilled in the art that othersuitable modifications and adaptations of the compositions and methodsof the invention described herein are evident and may be made withoutdeparting from the scope of the invention or the embodiments disclosedherein. Having now described the present invention in detail, the samewill be more clearly understood by reference to the following examples,which are included for purposes of illustration only and are notintended to be limiting of the invention.

DESCRIPTION OF FIGURES

[0251]FIG. 1 shows 6 selected pyridylpyrimidine derivatives which aresuitable inhibitors for prion diseases, namely compounds 4, 5, 37, 52,84, and 88;

[0252]FIG. 2 shows the compound4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide,also known as Gleevec™;

[0253]FIG. 3 shows selected compounds that have been identified aspotent inhibitors in a prion propagation assay at a concentration of 5μm.

EXAMPLES

[0254] Materials and Methods

[0255] 1. Generation of cDNA-Arrays on Membranes

[0256] In order to manufacture cDNAs-arrays on membranes, the followingstrategy was pursued: cDNAs encoding parts of or full length proteins ofinterest—in the following referred to as “target cDNAs”—were cloned intothe plasmid Bluescript II KS⁺ (Stratagene, USA). Large scalepurifications of these plasmids were performed according to standardtechniques and 200 μl aliquots (1 μg/μl plasmid concentration) weretransferred into appropriate 96well plates. Plates were closed withsealing tape and chilled on ice for 5 minutes after incubation for 10minutes at 95° C. 10 μl of 0.6 N NaOH were added and the mix was storedfor 20 minutes at room temperature before addition of 10 μl 2.5 MTris-HCl pH 7.1 and 20 μl 40×SSC (3 M NaCl, 300 mM Sodium Citrate, pH7.0). Target cDNAs were spotted onto Nylon or Nitrocellulose membranesusing a BioGrid (BioRobotics, UK) equipped with a 0.7 mm pintool. Inthis way, between 200 ng and 350 ng of plasmids encoding target cDNAswere transferred onto the membranes and crosslinked to the membranes byultraviolet light (1.2×10⁵ μJ/cm²). The arrays were stored for use insubsequent experiments at room temperature.

[0257] 2. Generation of Cells

[0258] PrP^(Sc)- and PrP^(c)-transfected mouse neuronal cells (N2A) werecultured in MEM (Minimum Essential Medium, Life Technologies)supplemented with 10% fetal calf serum at 37° C. and 5% CO₂ to obtain˜6×10⁶ cells per tissue culture flask.

[0259] 3. Lysis of Cells, Isolation of Total RNA and Purification ofPolyA⁺ RNA

[0260] After incubation of the cells with the virus for the respectivetime-points, cells were washed twice with phosphate buffered saline(PBS) and then trypsinized. Subsequently, cells were removed from theculture dish by resuspension with PBS. Afterwards, cells were sedimentedand directly lysed in Tri reagent by repetitive pipetting using in 1 mlof Tri reagent (Molecular Research Centre, Inc., USA) per 1×10⁶ cells.

[0261] The lysates were stored at room temperature for 5 minutes andthen centrifuged at 12000×g for 15 minutes at 4° C. The supernatant wasmixed with 0,1 ml of 1-bromo-3-chloropropane per 1 ml of Tri reagent andvigorously shaken. The suspension was stored for 5 minutes at roomtemperature and then centrifuged at 12000×g for 15 minutes at 4° C.

[0262] The colourless upper phase was transferred into new tubes, mixedwith 5 μl of poly-acryl-carrier (Molecular Research Centre, Inc., USA)and with 0.5 ml of isopropanol per 1 ml of Tri reagent and vigorouslyshaken. The samples were stored at room temperature for 5 minutes andthen centrifuged at 12000×g for 8 minutes at 4° C. The supernatant wasremoved and the RNA pellet washed twice with 1 ml of 75% ethanol. Thepellet was dried and resuspended for 10 minutes at 55° C. in 50 μl ofRNase-free buffer (5 mM Tris-HCl pH 7.5). The integrity of the isolatedRNA was determined by agarose/formaldehyde gel electrophoresis and theRNA was finally stored at −70° C. for use in subsequent experiments.

[0263] 4. Preparation of Radioactively Labelled cDNA Probes from RNA

[0264] In order to obtain radioactively labelled cDNA probes total RNAwas transcribed into a cDNA-probe in the presence of radioactivelylabelled dATP. 12 μl bidestilled DEPC (Diethylpyrocarbonate) treated H₂Ocontaining 0.5 μg of primer TXN (5′TTT TTT TTT TTT TTT TXN-3′ withT→dTTP; N→dATP, dCTP, dGTP or dTTP; X→dATP, dCTP or dGTP) and total RNA(1 to 10 μg) were shaken between 5 and 15′ at 60° C. and then incubatedon ice for 2 minutes. After centrifugation (30 seconds, 10000×g) 7 μl ofa mix consisting of 100 μCi dATP-P³³ (Amersham, UK) which were driedunder vacuum previously and resuspended in 4 μl first strand buffer(Life Technologies, USA), 2 μl 0.1M DTT (Dithiothreitol) and 1 μllabelling solution (4 mM dCTP, dGTP, dTTP each and 80 μM dATP finalconcentration) were added. Following the addition of 1 μl Superscript IIreverse transcriptase (Life Technologies, USA) the reaction wasincubated for 10 minutes at room temperature and then for 60 minutes at38° C. Subsequently, the reaction was vigorously shaken for 30 minutesat 68° C. after adding 5 μl 0.5 M EDTA and 25 μl 0.6M NaOH.

[0265] Unincorporated nucleotides were removed from the labellingreaction using ProbeQuant G-50 columns (Amersham, UK). The column wasvigorously shaken and centrifuged for 1 minute at 735×g in anappropriate reaction tube after bottom closure and lid were removed. Thecolumn was placed into a new reaction tube, the probe was applied ontothe centre of the column material and the column was centrifuged for 2minutes at 735×g. The flow-trough was transferred into new reactiontubes and filled up to a volume of 100 μl with bidestilled H₂O. Theprobe was precipitated by centrifugation for 15 minutes at 12000×g after4 μl 5M NaCl, 1 μl poly-acryl-carrier (Molecular Research Centre, Inc.,USA) and 250 μl ethanol were added. The supernatant was discarded andthe pellet was dried at 50° C. for 5 minutes before starting with thehybridisation.

[0266] 5. Hybridisation of Radioactively Labelled cDNA-Probes tocDNA-Arrays

[0267] The pellet was resuspended in 10 μl C₀T DNA (1 μg/μl, RocheDiagnostics, Germany), 10 μl yeast tRNA (1 μg/μl Sigma, USA) and 10 μlpolyA (1 μg/μl, Roche Diagnostics, Germany) and incubated at 55° C. for5 minutes. Herring sperm DNA was added to a final concentration of 100μg/ml and the volume was filled up to 100 μl with 5 μl 10% SDS(Sodiumdodecylsulfat), 25 μl 20×SSPE (3M Sodium chloride, 0,2 M Sodiumdihydrogen phosphate monohydrate, 0,02 M Ethylenedinitrilo tetraaceticacid, disodium salt dihydrate; pH 7,4 ) and bidestilled H₂O. The mix wasput on 95° C. for 5 minutes, centrifuged for 30 seconds at 10000×g andvigorously shaken for 60 minutes at 65° C. A 1 μl aliquot of the probewas used to measure the incorporation of radioactive dATP with ascintillation counter. Probes with at least a total of 20×10⁶ cpm wereused.

[0268] The arrays were prehybridised for at least 3 hours at 42° C. inhybridisation solution in a roller bottle oven. After prehybridizationthe radioactively labelled probe was added into the hybridisationsolution and hybridisation was continued for 20 to 40 hours.

[0269] The probe was discarded and replaced with wash solution A(2×SSC). The arrays were washed twice in wash solution A at roomtemperature in the roller oven. Afterwards, wash solution A was replacedby wash solution B (2×SSC, 0.5% SDS) preheated to 65° C. and arrays werewashed twice for 30 minutes at 65° C. Then, wash solution B was replacedby wash solution C (0.5×SSC, 0.5% SDS) preheated to 65° C. and arrayswere washed twice for 30 minutes at 65° C. The moist arrays were wrappedin airtight bags and exposed for 8 to 72 hours on erased phosphoimagerscreens (Fujifilm, Japan).

[0270] 6. Analysis of cDNA-Arrays

[0271] The exposed phosphoimager screens were scanned with a resolutionof 100μ and 16bits per pixel using a BAS-1800 (Fujifilm,,Japan). Fileswere imported into the computer program ArrayVision (Imaging Research,Canada). Using the program's features, the hybridization signals of eachtarget cDNA were converted into numbers. The strength of thehybridization signals reflected the quantity of RNA molecules present inthe probe. Differentially expressed genes were selected according to theratio of their signal strength after normalization to the overallintensity of the arrays.

[0272] 7. Cell Culture and Expression of 3F4-Tagged PrP (3F4-ScN2a)

[0273] The mouse neuroblastoma cell line 3F4-ScN2a represents a stablytransfected clone of ScN2a cells (PrP^(Sc) infected N2a cells) whichoverexpress 3F4-epitope-tagged murine PrP. Residues 109 and 112 ofmurine PrP were replaced by methionine to introduce the epitope forreactivity with the monoclonal anti-PrP antibody 3F4. Cells weremaintained in Dulbecco's modified Eagle's (DMEM) or Opti-MEM mediumcontaining 10% fetal calf serum, antibiotics and glutamin. Forgeneration of stable transfectants we used the vector pcDNA3.1/Zeo(Invitrogen; Leek, The Netherlands). Lipofection of cells withrecombinant plasmids was done using standard procedures and recombinantclones were selected by addition of 300 μg Zeocin/ml medium.

[0274] 8. Treatment of Cells with Inhibitors

[0275] All tested compounds were solubilized in DMSO(dimethylsulfoxide), and prepared as 10 mM stock solutions. The drugswere applied to the cells described above for three days in finalconcentrations between 5 and 20 μM.

[0276] 9. Immunoblot and Proteinase K (PK) Analysis

[0277] Confluent cell cultures were lysed in cold lysis buffer (10 mMTris-HCl, pH 7.5; 100 mM NaCl; 10 mM EDTA; 0.5% Triton X-100; 0.5% DOC)(EDTA: ethylene diamine tetraacetate; Triton X-100:t-octylphenoxypolyethoxyethanol; DOC: deoxycholic acid). Postnuclearlysates were split between those with and without proteinase Kdigestion. Samples without proteinase K digestion were supplemented withproteinase inhibitors (5 mM PMSF, 0.5 mM Pefabloc, and aprotinin) (PMSF:phenylmethylsulfonyl fluoride) and directly precipitated with ethanol.Samples for proteinase K digestion were incubated with 20 μg/mlproteinase K for 30 min at 37° C.; digestion was stopped with proteinaseinhibitors, and samples were ethanol precipitated. After centrifugingfor 30 min at 3,500 rpm the pellets were redissolved in TNE buffer (10mM Tris-HCl pH7.5, 100 mM NaCl, 1 mM EDTA) and gel loading buffer wasthen added. After boiling for 5 min an aliquot was analyzed on 12.5%PAGE. For Western blot analysis, the proteins were electrotransferred toPVDF membranes (polyvinylidendifluorid). The membrane was blocked with5% non-fat dry milk in TBST (0.05% Tween 20, 100 mM NaCl, 10 mMTris-HCl, pH 7.8) (Tween 20: polyoxyethylenesorbitan monolaurate;Tris-HCl: Tris-(hydroxymethyl)-aminomethane-hydrochloride), incubatedovernight with the primary antibody at 4° C. and stained using theenhanced chemiluminescence blotting kit from Amersham Corporation.Specific immuno-staining of the PrP^(c) and PrP^(Sc) forms were obtainedwith the prion protein specific antibody 3F4 (Signet Pathologies,U.S.A.).

[0278] 10. Results

[0279] Determination of the amount of the pathogenic form of the prionprotein PrP^(Sc) upon treatment of prion infected cells with differenttypes of small molecule protein kinase inhibitors resulted in theidentification of a compound class of pyridylpyrimidine derivativesexamplified by the compound4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny]-benzamide(compound 53) and compounds 4, 5, and 37.

[0280] These compounds significantly reduced the amount of PrP^(Sc) inprion infected cells in a concentration range between 5 and 20 μM (finalconcentration). As shown in FIG. 3 the selected compounds 4, 5, 37, and53 inhibit almost completely the activity of prion propagation withinsaid concentration range.

[0281] The compounds did not show any toxic effects on the cells inthese concentrations. Therefore these molecules described herein serveas potential inhibitors for the medical intervention of prion diseasessuch as transmissible spongiform encephalitis (TSE) infections whichinclude Bovine spongiform encephalitis (BSE) or the new variant ofCreutzfeld Jakob disease (vCJK).

1 20 1 2662 DNA Homo sapiens 1 tcagtttgaa aaggaggatc gagctcactcgtggagtatc catggagatg tggagccttg 60 tcaccaacct ctaactgcag aactgggatgtggagctgga agtgcctcct cttctgggct 120 gtgctggtca cagccacact ctgcaccgctaggccgtccc cgaccttgcc tgaacaagcc 180 cagccctggg gagcccctgt ggaagtggagtccttcctgg tccaccccgg tgacctgctg 240 cagcttcgct gtcggctgcg ggacgatgtgcagagcatca actggctgcg ggacggggtg 300 cagctggcgg aaagcaaccg cacccgcatcacaggggagg aggtggaggt gcaggactcc 360 gtgcccgcag actccggcct ctatgcttgcgtaaccagca gcccctcggg cagtgacacc 420 acctacttct ccgtcaatgt ttcagatgctctcccctcct cggaggatga tgatgatgat 480 gatgactcct cttcagagga gaaagaaacagataacacca aaccaaaccg tatgcccgta 540 gctccatatt ggacatcccc agaaaagatggaaaagaaat tgcatgcagt gccggctgcc 600 aagacagtga agttcaaatg cccttccagtgggaccccaa accccacact gcgctggttg 660 aaaaatggca aagaattcaa acctgaccacagaattggag gctacaaggt ccgttatgcc 720 acctggagca tcataatgga ctctgtggtgccctctgaca agggcaacta cacctgcatt 780 gtggagaatg agtacggcag catcaaccacacataccagc tggatgtcgt ggagcggtcc 840 cctcaccgcc ccatcctgca agcagggttgcccgccaaca aaacagtggc cctgggtagc 900 aacgtggagt tcatgtgtaa ggtgtacagtgacccgcagc cgcacatcca gtggctaaag 960 cacatcgagg tgaatgggag caagattggcccagacaacc tgccttatgt ccagatcttg 1020 aagactgctg gagttaatac caccgacaaagagatggagg tgcttcactt aagaaatgtc 1080 tcctttgagg acgcagggga gtatacgtgcttggcgggta actctatcgg actctcccat 1140 cactctgcat ggttgaccgt tctggaagccctggaagaga ggccggcagt gatgacctcg 1200 cccctgtacc tggagatcat catctattgcacaggggcct tcctcatctc ctgcatggtg 1260 gggtcggtca tcgtctacaa gatgaagagtggtaccaaga agagtgactt ccacagccag 1320 atggctgtgc acaagctggc caagagcatccctctgcgca gacaggtaac agtgtctgct 1380 gactccagtg catccatgaa ctctggggttcttctggttc ggccatcacg gctctcctcc 1440 agtgggactc ccatgctagc aggggtctctgagtatgagc ttcccgaaga ccctcgctgg 1500 gagctgcctc gggacagact ggtcttaggcaaacccctgg gagagggctg ctttgggcag 1560 gtggtgttgg cagaggctat cgggctggacaaggacaaac ccaaccgtgt gaccaaagtg 1620 gctgtgaaga tgttgaagtc ggacgcaacagagaaagact tgtcagacct gatctcagaa 1680 atggagatga tgaagatgat cgggaagcataagaatatca tcaacctgct gggggcctgc 1740 acgcaggatg gtcccttgta tgtcatcgtggagtatgcct ccaagggcaa cctgcgggag 1800 tacctgcagg cccggaggcc cccagggctggaatactgct acaaccccag ccacaaccca 1860 gaggagcagc tctcctccaa ggacctggtgtcctgcgcct accaggtggc ccgaggcatg 1920 gagtatctgg cctccaagaa gtgcatacaccgagacctgg cagccaggaa tgtcctggtg 1980 acagaggaca atgtgatgaa gatagcagactttggcctcg cacgggacat tcaccacatc 2040 gactactata aaaagacaac caacggccgactgcctgtga agtggatggc acccgaggca 2100 ttatttgacc ggatctacac ccaccagagtgatgtgtggt ctttcggggt gctcctgtgg 2160 gagatcttca ctctgggcgg ctccccataccccggtgtgc ctgtggagga acttttcaag 2220 ctgctgaagg agggtcaccg catggacaagcccagtaact gcaccaacga gctgtacatg 2280 atgatgcggg actgctggca tgcagtgccctcacagagac ccaccttcaa gcagctggtg 2340 gaagacctgg accgcatcgt ggccttgacctccaaccagg agtacctgga cctgtccatg 2400 cccctggacc agtactcccc cagctttcccgacacccgga gctctacgtg ctcctcaggg 2460 gaggattccg tcttctctca tgagccgctgcccgaggagc cctgcctgcc ccgacaccca 2520 gcccagcttg ccaatggcgg actcaaacgccgctgactgc cacccacacg ccctccccag 2580 actccaccgt cagctgtaac cctcacccacagcccctgcc tgggcccacc acctgtccgt 2640 ccctgtcccc tttcctgctg gg 2662 2822 PRT Homo sapiens 2 Met Trp Ser Trp Lys Cys Leu Leu Phe Trp Ala ValLeu Val Thr Ala 1 5 10 15 Thr Leu Cys Thr Ala Arg Pro Ser Pro Thr LeuPro Glu Gln Ala Gln 20 25 30 Pro Trp Gly Ala Pro Val Glu Val Glu Ser PheLeu Val His Pro Gly 35 40 45 Asp Leu Leu Gln Leu Arg Cys Arg Leu Arg AspAsp Val Gln Ser Ile 50 55 60 Asn Trp Leu Arg Asp Gly Val Gln Leu Ala GluSer Asn Arg Thr Arg 65 70 75 80 Ile Thr Gly Glu Glu Val Glu Val Gln AspSer Val Pro Ala Asp Ser 85 90 95 Gly Leu Tyr Ala Cys Val Thr Ser Ser ProSer Gly Ser Asp Thr Thr 100 105 110 Tyr Phe Ser Val Asn Val Ser Asp AlaLeu Pro Ser Ser Glu Asp Asp 115 120 125 Asp Asp Asp Asp Asp Ser Ser SerGlu Glu Lys Glu Thr Asp Asn Thr 130 135 140 Lys Pro Asn Arg Met Pro ValAla Pro Tyr Trp Thr Ser Pro Glu Lys 145 150 155 160 Met Glu Lys Lys LeuHis Ala Val Pro Ala Ala Lys Thr Val Lys Phe 165 170 175 Lys Cys Pro SerSer Gly Thr Pro Asn Pro Thr Leu Arg Trp Leu Lys 180 185 190 Asn Gly LysGlu Phe Lys Pro Asp His Arg Ile Gly Gly Tyr Lys Val 195 200 205 Arg TyrAla Thr Trp Ser Ile Ile Met Asp Ser Val Val Pro Ser Asp 210 215 220 LysGly Asn Tyr Thr Cys Ile Val Glu Asn Glu Tyr Gly Ser Ile Asn 225 230 235240 His Thr Tyr Gln Leu Asp Val Val Glu Arg Ser Pro His Arg Pro Ile 245250 255 Leu Gln Ala Gly Leu Pro Ala Asn Lys Thr Val Ala Leu Gly Ser Asn260 265 270 Val Glu Phe Met Cys Lys Val Tyr Ser Asp Pro Gln Pro His IleGln 275 280 285 Trp Leu Lys His Ile Glu Val Asn Gly Ser Lys Ile Gly ProAsp Asn 290 295 300 Leu Pro Tyr Val Gln Ile Leu Lys Thr Ala Gly Val AsnThr Thr Asp 305 310 315 320 Lys Glu Met Glu Val Leu His Leu Arg Asn ValSer Phe Glu Asp Ala 325 330 335 Gly Glu Tyr Thr Cys Leu Ala Gly Asn SerIle Gly Leu Ser His His 340 345 350 Ser Ala Trp Leu Thr Val Leu Glu AlaLeu Glu Glu Arg Pro Ala Val 355 360 365 Met Thr Ser Pro Leu Tyr Leu GluIle Ile Ile Tyr Cys Thr Gly Ala 370 375 380 Phe Leu Ile Ser Cys Met ValGly Ser Val Ile Val Tyr Lys Met Lys 385 390 395 400 Ser Gly Thr Lys LysSer Asp Phe His Ser Gln Met Ala Val His Lys 405 410 415 Leu Ala Lys SerIle Pro Leu Arg Arg Gln Val Thr Val Ser Ala Asp 420 425 430 Ser Ser AlaSer Met Asn Ser Gly Val Leu Leu Val Arg Pro Ser Arg 435 440 445 Leu SerSer Ser Gly Thr Pro Met Leu Ala Gly Val Ser Glu Tyr Glu 450 455 460 LeuPro Glu Asp Pro Arg Trp Glu Leu Pro Arg Asp Arg Leu Val Leu 465 470 475480 Gly Lys Pro Leu Gly Glu Gly Cys Phe Gly Gln Val Val Leu Ala Glu 485490 495 Ala Ile Gly Leu Asp Lys Asp Lys Pro Asn Arg Val Thr Lys Val Ala500 505 510 Val Lys Met Leu Lys Ser Asp Ala Thr Glu Lys Asp Leu Ser AspLeu 515 520 525 Ile Ser Glu Met Glu Met Met Lys Met Ile Gly Lys His LysAsn Ile 530 535 540 Ile Asn Leu Leu Gly Ala Cys Thr Gln Asp Gly Pro LeuTyr Val Ile 545 550 555 560 Val Glu Tyr Ala Ser Lys Gly Asn Leu Arg GluTyr Leu Gln Ala Arg 565 570 575 Arg Pro Pro Gly Leu Glu Tyr Cys Tyr AsnPro Ser His Asn Pro Glu 580 585 590 Glu Gln Leu Ser Ser Lys Asp Leu ValSer Cys Ala Tyr Gln Val Ala 595 600 605 Arg Gly Met Glu Tyr Leu Ala SerLys Lys Cys Ile His Arg Asp Leu 610 615 620 Ala Ala Arg Asn Val Leu ValThr Glu Asp Asn Val Met Lys Ile Ala 625 630 635 640 Asp Phe Gly Leu AlaArg Asp Ile His His Ile Asp Tyr Tyr Lys Lys 645 650 655 Thr Thr Asn GlyArg Leu Pro Val Lys Trp Met Ala Pro Glu Ala Leu 660 665 670 Phe Asp ArgIle Tyr Thr His Gln Ser Asp Val Trp Ser Phe Gly Val 675 680 685 Leu LeuTrp Glu Ile Phe Thr Leu Gly Gly Ser Pro Tyr Pro Gly Val 690 695 700 ProVal Glu Glu Leu Phe Lys Leu Leu Lys Glu Gly His Arg Met Asp 705 710 715720 Lys Pro Ser Asn Cys Thr Asn Glu Leu Tyr Met Met Met Arg Asp Cys 725730 735 Trp His Ala Val Pro Ser Gln Arg Pro Thr Phe Lys Gln Leu Val Glu740 745 750 Asp Leu Asp Arg Ile Val Ala Leu Thr Ser Asn Gln Glu Tyr LeuAsp 755 760 765 Leu Ser Met Pro Leu Asp Gln Tyr Ser Pro Ser Phe Pro AspThr Arg 770 775 780 Ser Ser Thr Cys Ser Ser Gly Glu Asp Ser Val Phe SerHis Glu Pro 785 790 795 800 Leu Pro Glu Glu Pro Cys Leu Pro Arg His ProAla Gln Leu Ala Asn 805 810 815 Gly Gly Leu Lys Arg Arg 820 3 3840 DNAHomo sapiens 3 ggccttcccc ctgcgaggat cgccgttggc ccgggttggc tttggaaagcggcggtggct 60 ttgggccggg ctcggcctcg ggaacgccag gggcccctgg gtgcggacgggcgcggccag 120 gagggggtta aggcgcaggc ggcggcgggg cgggggcggg cctggcgggcgccctctccg 180 ggccctttgt taacaggcgc gtcccggcca gcggagacgc ggccgccctgggcgggcgcg 240 ggcggcgggc ggcggtgagg gcggcctgcg gggcggcgcc cgggggccgggccgagccgg 300 gcctgagccg ggcccggacc gagctgggag aggggctccg gcccgatcgttcgcttggcg 360 caaaatgttg gagatctgcc tgaagctggt gggctgcaaa tccaagaaggggctgtcctc 420 gtcctccagc tgttatctgg aagaagccct tcagcggcca gtagcatctgactttgagcc 480 tcagggtctg agtgaagccg ctcgttggaa ctccaaggaa aaccttctcgctggacccag 540 tgaaaatgac cccaaccttt tcgttgcact gtatgatttt gtggccagtggagataacac 600 tctaagcata actaaaggtg aaaagctccg ggtcttaggc tataatcacaatggggaatg 660 gtgtgaagcc caaaccaaaa atggccaagg ctgggtccca agcaactacatcacgccagt 720 caacagtctg gagaaacact cctggtacca tgggcctgtg tcccgcaatgccgctgagta 780 tccgctgagc agcgggatca atggcagctt cttggtgcgt gagagtgagagcagtcctag 840 ccagaggtcc atctcgctga gatacgaagg gagggtgtac cattacaggatcaacactgc 900 ttctgatggc aagctctacg tctcctccga gagccgcttc aacaccctggccgagttggt 960 tcatcatcat tcaacggtgg ccgacgggct catcaccacg ctccattatccagccccaaa 1020 gcgcaacaag cccactgtct atggtgtgtc ccccaactac gacaagtgggagatggaacg 1080 cacggacatc accatgaagc acaagctggg cgggggccag tacggggaggtgtacgaggg 1140 cgtgtggaag aaatacagcc tgacggtggc cgtgaagacc ttgaaggaggacaccatgga 1200 ggtggaagag ttcttgaaag aagctgcagt catgaaagag atcaaacaccctaacctagt 1260 gcagctcctt ggggtctgca cccgggagcc cccgttctat atcatcactgagttcatgac 1320 ctacgggaac ctcctggact acctgaggga gtgcaaccgg caggaggtgaacgccgtggt 1380 gctgctgtac atggccactc agatctcgtc agccatggag tacctagagaagaaaaactt 1440 catccacaga gatcttgctg cccgaaactg cctggtaggg gagaaccacttggtgaaggt 1500 agctgatttt ggcctgagca ggttgatgac aggggacacc tacacagcccatgctggagc 1560 caagttcccc atcaaatgga ctgcacccga gagcctggcc tacaacaagttctccatcaa 1620 gtccgacgtc tgggcatttg gagtattgct ttgggaaatt gctacctatggcatgtcccc 1680 ttacccggga attgaccgtt cccaggtgta tgagctgcta gagaaggactaccgcatgaa 1740 gcgcccagaa ggctgcccag agaaggtcta tgaactcatg cgagcatgttggcagtggaa 1800 tccctctgac cggccctcct ttgctgaaat ccaccaagcc tttgaaacaatgttccagga 1860 atccagtatc tcagacgaag tggaaaagga gctggggaaa caaggcgtccgtggggctgt 1920 gactaccttg ctgcaggccc cagagctgcc caccaagacg aggacctccaggagagctgc 1980 agagcacaga gacaccactg acgtgcctga gatgcctcac tccaagggccagggagagag 2040 cgatcctctg gaccatgagc ctgccgtgtc tccattgctc cctcgaaaagagcgaggtcc 2100 cccggagggc ggcctgaatg aagatgagcg ccttctcccc aaagacaaaaagaccaactt 2160 gttcagcgcc ttgatcaaga agaagaagaa gacagcccca acccctcccaaacgcagcag 2220 ctccttccgg gagatggacg gccagccgga gcgcagaggg gccggcgaggaagagggccg 2280 agacatcagc aacggggcac tggctttcac ccccttggac acagctgacccagccaagtc 2340 cccaaagccc agcaatgggg ctggggtccc caatggagcc ctccgggagtccgggggctc 2400 aggcttccgg tctccccacc tgtggaagaa gtccagcacg ctgaccagcagccgcctagc 2460 caccggcgag gaggagggcg gtggcagctc cagcaagcgc ttcctgcgctcttgctccgt 2520 ctcctgcgtt ccccatgggg ccaaggacac ggagtggagg tcagtcacgctgcctcggga 2580 cttgcagtcc acgggaagac agtttgactc gtccacattt ggagggcacaaaagtgagaa 2640 gccggctctg cctcggaaga gggcagggga gaacaggtct gaccaggtgacccgaggcac 2700 agtaacgcct ccccccaggc tggtgaaaaa gaatgaggaa gctgctgatgaggtcttcaa 2760 agacatcatg gagtccagcc cgggctccag cccgcccaac ctgactccaaaacccctccg 2820 gcggcaggtc accgtggccc ctgcctcggg cctcccccac aaggaagaagcctggaaagg 2880 cagtgcctta gggacccctg ctgcagctga gccagtgacc cccaccagcaaagcaggctc 2940 aggtgcacca aggggcacca gcaagggccc cgccgaggag tccagagtgaggaggcacaa 3000 gcactcctct gagtcgccag ggagggacaa ggggaaattg tccaagctcaaacctgcccc 3060 gccgccccca ccagcagcct ctgcagggaa ggctggagga aagccctcgcagaggcccgg 3120 ccaggaggct gccggggagg cagtcttggg cgcaaagaca aaagccacgagtctggttga 3180 tgctgtgaac agtgacgctg ccaagcccag ccagccggca gagggcctcaaaaagcccgt 3240 gctcccggcc actccaaagc cacaccccgc caagccgtcg gggacccccatcagcccagc 3300 ccccgttccc ctttccacgt tgccatcagc atcctcggcc ttggcaggggaccagccgtc 3360 ttccactgcc ttcatccctc tcatatcaac ccgagtgtct cttcggaaaacccgccagcc 3420 tccagagcgg gccagcggcg ccatcaccaa gggcgtggtc ttggacagcaccgaggcgct 3480 gtgcctcgcc atctctggga actccgagca gatggccagc cacagcgcagtgctggaggc 3540 cggcaaaaac ctctacacgt tctgcgtgag ctatgtggat tccatccagcaaatgaggaa 3600 caagtttgcc ttccgagagg ccatcaacaa actggagaat aatctccgggagcttcagat 3660 ctgcccggcg tcagcaggca gtggtccggc ggccactcag gacttcagcaagctcctcag 3720 ttcggtgaag gaaatcagtg acatagtgca gaggtagcag cagtcaggggtcaggtgtca 3780 ggcccgtcgg agctgcctgc agcacatgcg ggctcgccca tacccatgacagtggctgag 3840 4 1130 PRT Homo sapiens 4 Met Leu Glu Ile Cys Leu LysLeu Val Gly Cys Lys Ser Lys Lys Gly 1 5 10 15 Leu Ser Ser Ser Ser SerCys Tyr Leu Glu Glu Ala Leu Gln Arg Pro 20 25 30 Val Ala Ser Asp Phe GluPro Gln Gly Leu Ser Glu Ala Ala Arg Trp 35 40 45 Asn Ser Lys Glu Asn LeuLeu Ala Gly Pro Ser Glu Asn Asp Pro Asn 50 55 60 Leu Phe Val Ala Leu TyrAsp Phe Val Ala Ser Gly Asp Asn Thr Leu 65 70 75 80 Ser Ile Thr Lys GlyGlu Lys Leu Arg Val Leu Gly Tyr Asn His Asn 85 90 95 Gly Glu Trp Cys GluAla Gln Thr Lys Asn Gly Gln Gly Trp Val Pro 100 105 110 Ser Asn Tyr IleThr Pro Val Asn Ser Leu Glu Lys His Ser Trp Tyr 115 120 125 His Gly ProVal Ser Arg Asn Ala Ala Glu Tyr Pro Leu Ser Ser Gly 130 135 140 Ile AsnGly Ser Phe Leu Val Arg Glu Ser Glu Ser Ser Pro Ser Gln 145 150 155 160Arg Ser Ile Ser Leu Arg Tyr Glu Gly Arg Val Tyr His Tyr Arg Ile 165 170175 Asn Thr Ala Ser Asp Gly Lys Leu Tyr Val Ser Ser Glu Ser Arg Phe 180185 190 Asn Thr Leu Ala Glu Leu Val His His His Ser Thr Val Ala Asp Gly195 200 205 Leu Ile Thr Thr Leu His Tyr Pro Ala Pro Lys Arg Asn Lys ProThr 210 215 220 Val Tyr Gly Val Ser Pro Asn Tyr Asp Lys Trp Glu Met GluArg Thr 225 230 235 240 Asp Ile Thr Met Lys His Lys Leu Gly Gly Gly GlnTyr Gly Glu Val 245 250 255 Tyr Glu Gly Val Trp Lys Lys Tyr Ser Leu ThrVal Ala Val Lys Thr 260 265 270 Leu Lys Glu Asp Thr Met Glu Val Glu GluPhe Leu Lys Glu Ala Ala 275 280 285 Val Met Lys Glu Ile Lys His Pro AsnLeu Val Gln Leu Leu Gly Val 290 295 300 Cys Thr Arg Glu Pro Pro Phe TyrIle Ile Thr Glu Phe Met Thr Tyr 305 310 315 320 Gly Asn Leu Leu Asp TyrLeu Arg Glu Cys Asn Arg Gln Glu Val Asn 325 330 335 Ala Val Val Leu LeuTyr Met Ala Thr Gln Ile Ser Ser Ala Met Glu 340 345 350 Tyr Leu Glu LysLys Asn Phe Ile His Arg Asp Leu Ala Ala Arg Asn 355 360 365 Cys Leu ValGly Glu Asn His Leu Val Lys Val Ala Asp Phe Gly Leu 370 375 380 Ser ArgLeu Met Thr Gly Asp Thr Tyr Thr Ala His Ala Gly Ala Lys 385 390 395 400Phe Pro Ile Lys Trp Thr Ala Pro Glu Ser Leu Ala Tyr Asn Lys Phe 405 410415 Ser Ile Lys Ser Asp Val Trp Ala Phe Gly Val Leu Leu Trp Glu Ile 420425 430 Ala Thr Tyr Gly Met Ser Pro Tyr Pro Gly Ile Asp Arg Ser Gln Val435 440 445 Tyr Glu Leu Leu Glu Lys Asp Tyr Arg Met Lys Arg Pro Glu GlyCys 450 455 460 Pro Glu Lys Val Tyr Glu Leu Met Arg Ala Cys Trp Gln TrpAsn Pro 465 470 475 480 Ser Asp Arg Pro Ser Phe Ala Glu Ile His Gln AlaPhe Glu Thr Met 485 490 495 Phe Gln Glu Ser Ser Ile Ser Asp Glu Val GluLys Glu Leu Gly Lys 500 505 510 Gln Gly Val Arg Gly Ala Val Thr Thr LeuLeu Gln Ala Pro Glu Leu 515 520 525 Pro Thr Lys Thr Arg Thr Ser Arg ArgAla Ala Glu His Arg Asp Thr 530 535 540 Thr Asp Val Pro Glu Met Pro HisSer Lys Gly Gln Gly Glu Ser Asp 545 550 555 560 Pro Leu Asp His Glu ProAla Val Ser Pro Leu Leu Pro Arg Lys Glu 565 570 575 Arg Gly Pro Pro GluGly Gly Leu Asn Glu Asp Glu Arg Leu Leu Pro 580 585 590 Lys Asp Lys LysThr Asn Leu Phe Ser Ala Leu Ile Lys Lys Lys Lys 595 600 605 Lys Thr AlaPro Thr Pro Pro Lys Arg Ser Ser Ser Phe Arg Glu Met 610 615 620 Asp GlyGln Pro Glu Arg Arg Gly Ala Gly Glu Glu Glu Gly Arg Asp 625 630 635 640Ile Ser Asn Gly Ala Leu Ala Phe Thr Pro Leu Asp Thr Ala Asp Pro 645 650655 Ala Lys Ser Pro Lys Pro Ser Asn Gly Ala Gly Val Pro Asn Gly Ala 660665 670 Leu Arg Glu Ser Gly Gly Ser Gly Phe Arg Ser Pro His Leu Trp Lys675 680 685 Lys Ser Ser Thr Leu Thr Ser Ser Arg Leu Ala Thr Gly Glu GluGlu 690 695 700 Gly Gly Gly Ser Ser Ser Lys Arg Phe Leu Arg Ser Cys SerVal Ser 705 710 715 720 Cys Val Pro His Gly Ala Lys Asp Thr Glu Trp ArgSer Val Thr Leu 725 730 735 Pro Arg Asp Leu Gln Ser Thr Gly Arg Gln PheAsp Ser Ser Thr Phe 740 745 750 Gly Gly His Lys Ser Glu Lys Pro Ala LeuPro Arg Lys Arg Ala Gly 755 760 765 Glu Asn Arg Ser Asp Gln Val Thr ArgGly Thr Val Thr Pro Pro Pro 770 775 780 Arg Leu Val Lys Lys Asn Glu GluAla Ala Asp Glu Val Phe Lys Asp 785 790 795 800 Ile Met Glu Ser Ser ProGly Ser Ser Pro Pro Asn Leu Thr Pro Lys 805 810 815 Pro Leu Arg Arg GlnVal Thr Val Ala Pro Ala Ser Gly Leu Pro His 820 825 830 Lys Glu Glu AlaTrp Lys Gly Ser Ala Leu Gly Thr Pro Ala Ala Ala 835 840 845 Glu Pro ValThr Pro Thr Ser Lys Ala Gly Ser Gly Ala Pro Arg Gly 850 855 860 Thr SerLys Gly Pro Ala Glu Glu Ser Arg Val Arg Arg His Lys His 865 870 875 880Ser Ser Glu Ser Pro Gly Arg Asp Lys Gly Lys Leu Ser Lys Leu Lys 885 890895 Pro Ala Pro Pro Pro Pro Pro Ala Ala Ser Ala Gly Lys Ala Gly Gly 900905 910 Lys Pro Ser Gln Arg Pro Gly Gln Glu Ala Ala Gly Glu Ala Val Leu915 920 925 Gly Ala Lys Thr Lys Ala Thr Ser Leu Val Asp Ala Val Asn SerAsp 930 935 940 Ala Ala Lys Pro Ser Gln Pro Ala Glu Gly Leu Lys Lys ProVal Leu 945 950 955 960 Pro Ala Thr Pro Lys Pro His Pro Ala Lys Pro SerGly Thr Pro Ile 965 970 975 Ser Pro Ala Pro Val Pro Leu Ser Thr Leu ProSer Ala Ser Ser Ala 980 985 990 Leu Ala Gly Asp Gln Pro Ser Ser Thr AlaPhe Ile Pro Leu Ile Ser 995 1000 1005 Thr Arg Val Ser Leu Arg Lys ThrArg Gln Pro Pro Glu Arg Ala 1010 1015 1020 Ser Gly Ala Ile Thr Lys GlyVal Val Leu Asp Ser Thr Glu Ala 1025 1030 1035 Leu Cys Leu Ala Ile SerGly Asn Ser Glu Gln Met Ala Ser His 1040 1045 1050 Ser Ala Val Leu GluAla Gly Lys Asn Leu Tyr Thr Phe Cys Val 1055 1060 1065 Ser Tyr Val AspSer Ile Gln Gln Met Arg Asn Lys Phe Ala Phe 1070 1075 1080 Arg Glu AlaIle Asn Lys Leu Glu Asn Asn Leu Arg Glu Leu Gln 1085 1090 1095 Ile CysPro Ala Ser Ala Gly Ser Gly Pro Ala Ala Thr Gln Asp 1100 1105 1110 PheSer Lys Leu Leu Ser Ser Val Lys Glu Ile Ser Asp Ile Val 1115 1120 1125Gln Arg 1130 5 1461 DNA Homo sapiens 5 aggcggtgtt tgtctgccgg actgacgggcggccgggcgg tgcgcggcgg cggtggcggc 60 ggggaaaatg gcggcgtcct ccctggaacagaagctgtcc cgcctggaag caaagctgaa 120 gcaggagaac cgggaggccc ggcggaggatcgacctcaac ctggatatca gcccccagcg 180 gcccaggccc accctgcagc tcccgctggccaacgatggg ggcagccgct cgccatcctc 240 agagagctcc ccgcagcacc ccacgccccccgcccggccc cgccacatgc tggggctccc 300 gtcaaccctg ttcacacccc gcagcatggagagcattgag attgaccaga agctgcagga 360 gatcatgaag cagacgggct acctgaccatcgggggccag cgctaccagg cagaaatcaa 420 cgacctggag aacttgggcg agatgggcagcggcacctgc ggccaggtgt ggaagatgcg 480 cttccggaag accggccacg tcattgccgttaagcaaatg cggcgctccg ggaacaagga 540 ggagaacaag cgcatcctca tggacctggatgtggtgctg aagagccacg actgccccta 600 catcgtgcag tgctttggga cgttcatcaccaacacggac gtcttcatcg ccatggagct 660 catgggcacc tgcgctgaga agctcaagaagcggatgcag ggccccatcc ccgagcgcat 720 tctgggcaag atgacagtgg cgattgtgaaggcgctgtac tacctgaagg agaagcacgg 780 tgtcatccac cgcgacgtca agccctccaacatcctgctg gacgagcggg gccagatcaa 840 gttctgcgac ttcggcatca gcggccgcctggtggactcc aaagccaaga cgcggagcgc 900 cggctgtgcc gcctacatgg cacccgagcgcattgacccc ccagacccca ccaagccgga 960 ctatgacatc cgggccgacg tatggagcctgggcatctcg ctggtggagc tggcaacagg 1020 acagtttccc tacaagaact gcaagacggactttgaggtc ctcaccaaag tcctacagga 1080 agagcccccg cttctgcccg gacacatgggcttctcgggg gacttccagt ccttcgtcaa 1140 agactgcctt actaaagatc acaggaagagaccaaagtat aataagctac ttgaacacag 1200 cttcatcaag cgctacgaga cgctggaggtggacgtggcg tcctggttca aggatgtcat 1260 ggcgaagact gagtcaccgc ggactagcggcgtcctgagc cagccccacc tgcccttctt 1320 caggtagctg cttggcggcg gccagccccacagggggcca ggggcatggc cacaggcccc 1380 cctccccact tggccaccca gctgcctgccaggggagacc tgggacctgg acggccacct 1440 aggactgagg acagagagtg g 1461 6 419PRT Homo sapiens 6 Met Ala Ala Ser Ser Leu Glu Gln Lys Leu Ser Arg LeuGlu Ala Lys 1 5 10 15 Leu Lys Gln Glu Asn Arg Glu Ala Arg Arg Arg IleAsp Leu Asn Leu 20 25 30 Asp Ile Ser Pro Gln Arg Pro Arg Pro Thr Leu GlnLeu Pro Leu Ala 35 40 45 Asn Asp Gly Gly Ser Arg Ser Pro Ser Ser Glu SerSer Pro Gln His 50 55 60 Pro Thr Pro Pro Ala Arg Pro Arg His Met Leu GlyLeu Pro Ser Thr 65 70 75 80 Leu Phe Thr Pro Arg Ser Met Glu Ser Ile GluIle Asp Gln Lys Leu 85 90 95 Gln Glu Ile Met Lys Gln Thr Gly Tyr Leu ThrIle Gly Gly Gln Arg 100 105 110 Tyr Gln Ala Glu Ile Asn Asp Leu Glu AsnLeu Gly Glu Met Gly Ser 115 120 125 Gly Thr Cys Gly Gln Val Trp Lys MetArg Phe Arg Lys Thr Gly His 130 135 140 Val Ile Ala Val Lys Gln Met ArgArg Ser Gly Asn Lys Glu Glu Asn 145 150 155 160 Lys Arg Ile Leu Met AspLeu Asp Val Val Leu Lys Ser His Asp Cys 165 170 175 Pro Tyr Ile Val GlnCys Phe Gly Thr Phe Ile Thr Asn Thr Asp Val 180 185 190 Phe Ile Ala MetGlu Leu Met Gly Thr Cys Ala Glu Lys Leu Lys Lys 195 200 205 Arg Met GlnGly Pro Ile Pro Glu Arg Ile Leu Gly Lys Met Thr Val 210 215 220 Ala IleVal Lys Ala Leu Tyr Tyr Leu Lys Glu Lys His Gly Val Ile 225 230 235 240His Arg Asp Val Lys Pro Ser Asn Ile Leu Leu Asp Glu Arg Gly Gln 245 250255 Ile Lys Phe Cys Asp Phe Gly Ile Ser Gly Arg Leu Val Asp Ser Lys 260265 270 Ala Lys Thr Arg Ser Ala Gly Cys Ala Ala Tyr Met Ala Pro Glu Arg275 280 285 Ile Asp Pro Pro Asp Pro Thr Lys Pro Asp Tyr Asp Ile Arg AlaAsp 290 295 300 Val Trp Ser Leu Gly Ile Ser Leu Val Glu Leu Ala Thr GlyGln Phe 305 310 315 320 Pro Tyr Lys Asn Cys Lys Thr Asp Phe Glu Val LeuThr Lys Val Leu 325 330 335 Gln Glu Glu Pro Pro Leu Leu Pro Gly His MetGly Phe Ser Gly Asp 340 345 350 Phe Gln Ser Phe Val Lys Asp Cys Leu ThrLys Asp His Arg Lys Arg 355 360 365 Pro Lys Tyr Asn Lys Leu Leu Glu HisSer Phe Ile Lys Arg Tyr Glu 370 375 380 Thr Leu Glu Val Asp Val Ala SerTrp Phe Lys Asp Val Met Ala Lys 385 390 395 400 Thr Glu Ser Pro Arg ThrSer Gly Val Leu Ser Gln Pro His Leu Pro 405 410 415 Phe Phe Arg 7 1050DNA Homo sapiens 7 gggggggggg ggcacttggc ttcaaagctg gctcttggaaattgagcgga gacgagcggc 60 ttgttgtagc tgccgtgcgg ccgccgcgga ataataagccgggatctacc ataccattga 120 ctaactatgg aagattatac caaaatagag aaaattggagaaggtaccta tggagttgtg 180 tataagggta gacacaaaac tacaggtcaa gtggtagccatgaaaaaaat cagactagaa 240 agtgaagagg aaggggttcc tagtactgca attcgggaaatttctctatt aaaggaactt 300 cgtcatccaa atatagtcag tcttcaggat gtgcttatgcaggattccag gttatatctc 360 atctttgagt ttctttccat ggatctgaag aaatacttggattctatccc tcctggtcag 420 tacatggatt cttcacttgt taagagttat ttataccaaatcctacaggg gattgtgttt 480 tgtcactcta gaagagttct tcacagagac ttaaaacctcaaaatctctt gattgatgac 540 aaaggaacaa ttaaactggc tgattttggc cttgccagagcttttggaat acctatcaga 600 gtatatacac atgaggtagt aacactctgg tacagatctccagaagtatt gctggggtca 660 gctcgttact caactccagt tgacatttgg agtataggcaccatatttgc tgaactagca 720 actaagaaac cacttttcca tggggattca gaaattgatcaactcttcag gattttcaga 780 gctttgggca ctcccaataa tgaagtgtgg ccagaagtggaatctttaca ggactataag 840 aatacatttc ccaaatggaa accaggaagc ctagcatcccatgtcaaaaa cttggatgaa 900 aatggcttgg atttgctctc gaaaatgtta atctatgatccagccaaacg aatttctggc 960 aaaatggcac tgaatcatcc atattttaat gatttggacaatcagattaa gaagatgtag 1020 ctttctgaca aaaagtttcc atatgttatg 1050 8 297PRT Homo sapiens 8 Met Glu Asp Tyr Thr Lys Ile Glu Lys Ile Gly Glu GlyThr Tyr Gly 1 5 10 15 Val Val Tyr Lys Gly Arg His Lys Thr Thr Gly GlnVal Val Ala Met 20 25 30 Lys Lys Ile Arg Leu Glu Ser Glu Glu Glu Gly ValPro Ser Thr Ala 35 40 45 Ile Arg Glu Ile Ser Leu Leu Lys Glu Leu Arg HisPro Asn Ile Val 50 55 60 Ser Leu Gln Asp Val Leu Met Gln Asp Ser Arg LeuTyr Leu Ile Phe 65 70 75 80 Glu Phe Leu Ser Met Asp Leu Lys Lys Tyr LeuAsp Ser Ile Pro Pro 85 90 95 Gly Gln Tyr Met Asp Ser Ser Leu Val Lys SerTyr Leu Tyr Gln Ile 100 105 110 Leu Gln Gly Ile Val Phe Cys His Ser ArgArg Val Leu His Arg Asp 115 120 125 Leu Lys Pro Gln Asn Leu Leu Ile AspAsp Lys Gly Thr Ile Lys Leu 130 135 140 Ala Asp Phe Gly Leu Ala Arg AlaPhe Gly Ile Pro Ile Arg Val Tyr 145 150 155 160 Thr His Glu Val Val ThrLeu Trp Tyr Arg Ser Pro Glu Val Leu Leu 165 170 175 Gly Ser Ala Arg TyrSer Thr Pro Val Asp Ile Trp Ser Ile Gly Thr 180 185 190 Ile Phe Ala GluLeu Ala Thr Lys Lys Pro Leu Phe His Gly Asp Ser 195 200 205 Glu Ile AspGln Leu Phe Arg Ile Phe Arg Ala Leu Gly Thr Pro Asn 210 215 220 Asn GluVal Trp Pro Glu Val Glu Ser Leu Gln Asp Tyr Lys Asn Thr 225 230 235 240Phe Pro Lys Trp Lys Pro Gly Ser Leu Ala Ser His Val Lys Asn Leu 245 250255 Asp Glu Asn Gly Leu Asp Leu Leu Ser Lys Met Leu Ile Tyr Asp Pro 260265 270 Ala Lys Arg Ile Ser Gly Lys Met Ala Leu Asn His Pro Tyr Phe Asn275 280 285 Asp Leu Asp Asn Gln Ile Lys Lys Met 290 295 9 1480 DNA Homosapiens misc_feature (104)..(106) n = a, c, g or t 9 gaattccgagcaagagcgcg ggcgggtggc ccaggcacgc agcgggtgag gaccgcgccc 60 acagctcggcgccaaccacc gcgggcctcc cagccagccc cgcnnngagc cgcaggancc 120 ctggctgtggtcggggggca gtgggccatg ctgggggcag tggaaggccc caggtggaag 180 caggcggaggacattagaga catctacgac ttccgagatg ttctgggcac gggggccttc 240 tcggaggtgatcctggcaga agataagagg acgcagaagc tggtggccat caaatgcatt 300 gccaaggaggccctggaggg caaggaaggc agcatggaga atgagattgc tgtcctgcac 360 aagatcaagcaccccaacat tgtagccctg gatgacatct atgagagtgg gggccacctc 420 tacctcatcatgcagctggt gtcgggtggg gagctctttg accgtattgt ggaaaaaggc 480 ttctacacggagcgggacgc cagccgcctc atcttccagg tgctggatgc tgtgaaatac 540 ctgcatgacctgggcattgt acaccgggat ctcaagccag agaatctgct gtactacagc 600 ctggatgaagactccaaaat catgatctcc gactttggcc tctccaagat ggaggacccg 660 ggcagtgtgctctccaccgc ctgtggaact ccgggatacg tggcccctga agtcctggcc 720 cagaagccctacagcaaggc tgtggattgc tggtccatag gtgtcatcgc ctacatcttg 780 ctctgcggttaccctccctt ctatgacgag aatgatgcca aactctttga acagattttg 840 aaggccgagtacgagtttga ctctccttac tgggacgaca tctctgactc tgccaaagat 900 ttcatccggcacttgatgga gaaggaccca gagaaaagat tcacctgtga gcaggccttg 960 cagcacccatggattgcagg agatacagct ctagataaga atatccacca gtcggtgagt 1020 gagcagatcaagaagaactt tgccaagagc aagtggaagc aagccttcaa tgccacggct 1080 gtggtgcggcacatgaggaa actgcagctg ggcaccagcc aggaggggca ggggcagacg 1140 gcgagccatggggagctgct gacaccagtg gctggggggc cggcagctgg ctgttgctgt 1200 cgagactgctgcgtggagcc gggcacagaa ctgtccccca cactgcccca ccagctctag 1260 ggccctggacctcgggtcat gatcctctgc gtgggagggc ttgggggcca gcctgctccc 1320 cttccctccctgaaccggga gtttctctgc cctgtcccct cctcacctgc ttccctacca 1380 ctcctcactgcattttccat acaaatgttt ctattttatt gttccttctt gtaataaagg 1440 gaagataaaaccaaaaaaaa aaaaaaaaaa acggaattcc 1480 10 370 PRT Homo sapiens 10 Met LeuGly Ala Val Glu Gly Pro Arg Trp Lys Gln Ala Glu Asp Ile 1 5 10 15 ArgAsp Ile Tyr Asp Phe Arg Asp Val Leu Gly Thr Gly Ala Phe Ser 20 25 30 GluVal Ile Leu Ala Glu Asp Lys Arg Thr Gln Lys Leu Val Ala Ile 35 40 45 LysCys Ile Ala Lys Glu Ala Leu Glu Gly Lys Glu Gly Ser Met Glu 50 55 60 AsnGlu Ile Ala Val Leu His Lys Ile Lys His Pro Asn Ile Val Ala 65 70 75 80Leu Asp Asp Ile Tyr Glu Ser Gly Gly His Leu Tyr Leu Ile Met Gln 85 90 95Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Val Glu Lys Gly Phe 100 105110 Tyr Thr Glu Arg Asp Ala Ser Arg Leu Ile Phe Gln Val Leu Asp Ala 115120 125 Val Lys Tyr Leu His Asp Leu Gly Ile Val His Arg Asp Leu Lys Pro130 135 140 Glu Asn Leu Leu Tyr Tyr Ser Leu Asp Glu Asp Ser Lys Ile MetIle 145 150 155 160 Ser Asp Phe Gly Leu Ser Lys Met Glu Asp Pro Gly SerVal Leu Ser 165 170 175 Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro GluVal Leu Ala Gln 180 185 190 Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp SerIle Gly Val Ile Ala 195 200 205 Tyr Ile Leu Leu Cys Gly Tyr Pro Pro PheTyr Asp Glu Asn Asp Ala 210 215 220 Lys Leu Phe Glu Gln Ile Leu Lys AlaGlu Tyr Glu Phe Asp Ser Pro 225 230 235 240 Tyr Trp Asp Asp Ile Ser AspSer Ala Lys Asp Phe Ile Arg His Leu 245 250 255 Met Glu Lys Asp Pro GluLys Arg Phe Thr Cys Glu Gln Ala Leu Gln 260 265 270 His Pro Trp Ile AlaGly Asp Thr Ala Leu Asp Lys Asn Ile His Gln 275 280 285 Ser Val Ser GluGln Ile Lys Lys Asn Phe Ala Lys Ser Lys Trp Lys 290 295 300 Gln Ala PheAsn Ala Thr Ala Val Val Arg His Met Arg Lys Leu Gln 305 310 315 320 LeuGly Thr Ser Gln Glu Gly Gln Gly Gln Thr Ala Ser His Gly Glu 325 330 335Leu Leu Thr Pro Val Ala Gly Gly Pro Ala Ala Gly Cys Cys Cys Arg 340 345350 Asp Cys Cys Val Glu Pro Gly Thr Glu Leu Ser Pro Thr Leu Pro His 355360 365 Gln Leu 370 11 1782 DNA Homo sapiens 11 gggcgggcga gggatctgaaacttgcccac ccttcgggat attgcaggac gctgcatcat 60 gagcgacagt aaatgtgacagtcagtttta tagtgtgcaa gtggcagact caaccttcac 120 tgtcctaaaa cgttaccagcagctgaaacc aattggctct ggggcccaag ggattgtttg 180 tgctgcattt gatacagttcttgggataag tgttgcagtc aagaaactaa gccgtccttt 240 tcagaaccaa actcatgcaaagagagctta tcgtgaactt gtcctcttaa aatgtgtcaa 300 tcataaaaat ataattagtttgttaaatgt gtttacacca caaaaaactc tagaagaatt 360 tcaagatgtg tatttggttatggaattaat ggatgctaac ttatgtcagg ttattcacat 420 ggagctggat catgaaagaatgtcctacct tctttaccag atgctttgtg gtattaaaca 480 tctgcattca gctggtataattcatagaga tttgaagcct agcaacattg ttgtgaaatc 540 agactgcacc ctgaagatccttgactttgg cctggcccgg acagcgtgca ctaacttcat 600 gatgacccct tacgtggtgacacggtacta ccgggcgccc gaagtcatcc tgggtatggg 660 ctacaaagag aacgttgatatctggtcagt gggttgcatc atgggagagc tggtgaaagg 720 ttgtgtgata ttccaaggcactgaccatat tgatcagtgg aataaagtta ttgagcagct 780 gggaacacca tcagcagagttcatgaagaa acttcagcca actgtgagga attatgtcga 840 aaacagacca aagtatcctggaatcaaatt tgaagaactc tttccagatt ggatattccc 900 atcagaatct gagcgagacaaaataaaaac aagtcaagcc agagatctgt tatcaaaaat 960 gttagtgatt gatcctgacaagcggatctc tgtagacgaa gctctgcgtc acccatacat 1020 cactgtttgg tatgaccccgccgaagcaga agccccacca cctcaaattt atgatgccca 1080 gttggaagaa agagaacatgcaattgaaga atggaaagag ctaatttaca aagaagtcat 1140 ggattgggaa gaaagaagcaagaatggtgt tgtaaaagat cagccttcag atgcagcagt 1200 aagtagcaac gccactccttctcagtcttc atcgatcaat gacatttcat ccatgtccac 1260 tgagcagacg ctggcctcagacacagacag cagtcttgat gcctcgacgg gaccccttga 1320 aggctgtcga tgataggttagaaatagcaa acctgtcagc attgaaggaa ctctcacctc 1380 cgtgggcctg aaatgcttgggagttgatgg aaccaaatag aaaaactcca tgttctgcat 1440 gtaagaaaca caatgccttgccctattcag acctgatagg attgcctgct tagatgataa 1500 aatgaggcag aatatgtctgaagaaaaaaa ttgcaagcca cacttctaga gattttgttc 1560 aagatcattt caggtgagcagttagagtag gtgaatttgt ttcaaattgt actagtgaca 1620 gtttctcatc atctgtaactgttgagatgt atgtgcatgt gaccacaaat gcttgcttgg 1680 acttgcccat ctagcactttggaaatcagt atttaaatgc caaataatct tccaggtagt 1740 gctgcttctg aagttatctcttaatcctct taagtaattt gg 1782 12 424 PRT Homo sapiens 12 Met Ser Asp SerLys Cys Asp Ser Gln Phe Tyr Ser Val Gln Val Ala 1 5 10 15 Asp Ser ThrPhe Thr Val Leu Lys Arg Tyr Gln Gln Leu Lys Pro Ile 20 25 30 Gly Ser GlyAla Gln Gly Ile Val Cys Ala Ala Phe Asp Thr Val Leu 35 40 45 Gly Ile SerVal Ala Val Lys Lys Leu Ser Arg Pro Phe Gln Asn Gln 50 55 60 Thr His AlaLys Arg Ala Tyr Arg Glu Leu Val Leu Leu Lys Cys Val 65 70 75 80 Asn HisLys Asn Ile Ile Ser Leu Leu Asn Val Phe Thr Pro Gln Lys 85 90 95 Thr LeuGlu Glu Phe Gln Asp Val Tyr Leu Val Met Glu Leu Met Asp 100 105 110 AlaAsn Leu Cys Gln Val Ile His Met Glu Leu Asp His Glu Arg Met 115 120 125Ser Tyr Leu Leu Tyr Gln Met Leu Cys Gly Ile Lys His Leu His Ser 130 135140 Ala Gly Ile Ile His Arg Asp Leu Lys Pro Ser Asn Ile Val Val Lys 145150 155 160 Ser Asp Cys Thr Leu Lys Ile Leu Asp Phe Gly Leu Ala Arg ThrAla 165 170 175 Cys Thr Asn Phe Met Met Thr Pro Tyr Val Val Thr Arg TyrTyr Arg 180 185 190 Ala Pro Glu Val Ile Leu Gly Met Gly Tyr Lys Glu AsnVal Asp Ile 195 200 205 Trp Ser Val Gly Cys Ile Met Gly Glu Leu Val LysGly Cys Val Ile 210 215 220 Phe Gln Gly Thr Asp His Ile Asp Gln Trp AsnLys Val Ile Glu Gln 225 230 235 240 Leu Gly Thr Pro Ser Ala Glu Phe MetLys Lys Leu Gln Pro Thr Val 245 250 255 Arg Asn Tyr Val Glu Asn Arg ProLys Tyr Pro Gly Ile Lys Phe Glu 260 265 270 Glu Leu Phe Pro Asp Trp IlePhe Pro Ser Glu Ser Glu Arg Asp Lys 275 280 285 Ile Lys Thr Ser Gln AlaArg Asp Leu Leu Ser Lys Met Leu Val Ile 290 295 300 Asp Pro Asp Lys ArgIle Ser Val Asp Glu Ala Leu Arg His Pro Tyr 305 310 315 320 Ile Thr ValTrp Tyr Asp Pro Ala Glu Ala Glu Ala Pro Pro Pro Gln 325 330 335 Ile TyrAsp Ala Gln Leu Glu Glu Arg Glu His Ala Ile Glu Glu Trp 340 345 350 LysGlu Leu Ile Tyr Lys Glu Val Met Asp Trp Glu Glu Arg Ser Lys 355 360 365Asn Gly Val Val Lys Asp Gln Pro Ser Asp Ala Ala Val Ser Ser Asn 370 375380 Ala Thr Pro Ser Gln Ser Ser Ser Ile Asn Asp Ile Ser Ser Met Ser 385390 395 400 Thr Glu Gln Thr Leu Ala Ser Asp Thr Asp Ser Ser Leu Asp AlaSer 405 410 415 Thr Gly Pro Leu Glu Gly Cys Arg 420 13 3668 DNA Homosapiens 13 gtggtcttcc cgcgcctgag gcggcggcgg caggagctga ggggagttgtagggaactga 60 ggggagctgc tgtgtccccc gcctcctcct ccccatttcc gggctcccgggaccatgtcc 120 gcgctggcgg gtgaagatgt ctggaggtgt ccaggctgtg gggaccacattgctccaagc 180 cagatatggt acaggactgt caacgaaacc tggcacggct cttgcttccggtgttcagaa 240 tgccaggatt ccctcaccaa ctggtactat gagaaggatg ggaagctctactgccccaag 300 gactactggg ggaagtttgg ggagttctgt catgggtgct ccctgctgatgacagggcct 360 tttatggtgg ctggggagtt caagtaccac ccagagtgct ttgcctgtatgagctgcaag 420 gtgatcattg aggatgggga tgcatatgca ctggtgcagc atgccaccctctactgtggg 480 aagtgccaca atgaggtggt gctggcaccc atgtttgaga gactctccacagagtctgtt 540 caggagcagc tgccctactc tgtcacgctc atctccatgc cggccaccactgaaggcagg 600 cggggcttct ccgtgtccgt ggagagtgcc tgctccaact acgccaccactgtgcaagtg 660 aaagaggtca accggatgca catcagtccc aacaatcgaa acgccatccaccctggggac 720 cgcatcctgg agatcaatgg gacccccgtc cgcacacttc gagtggaggaggtggaggat 780 gcaattagcc agacgagcca gacacttcag ctgttgattg aacatgaccccgtctcccaa 840 cgcctggacc agctgcggct ggaggcccgg ctcgctcctc acatgcagaatgccggacac 900 ccccacgccc tcagcaccct ggacaccaag gagaatctgg aggggacactgaggagacgt 960 tccctaaggc gcagtaacag tatctccaag tcccctggcc ccagctccccaaaggagccc 1020 ctgctgttca gccgtgacat cagccgctca gaatcccttc gttgttccagcagctattca 1080 cagcagatct tccggccctg tgacctaatc catggggagg tcctggggaagggcttcttt 1140 gggcaggcta tcaaggtgac acacaaagcc acgggcaaag tgatggtcatgaaagagtta 1200 attcgatgtg atgaggagac ccagaaaact tttctgactg aggtgaaagtgatgcgcagc 1260 ctggaccacc ccaatgtgct caagttcatt ggtgtgctgt acaaggataagaagctgaac 1320 ctgctgacag agtacattga ggggggcaca ctgaaggact ttctgcgcagtatggatccg 1380 ttcccctggc agcagaaggt caggtttgcc aaaggaatcg cctccggaatggcctatttg 1440 cactctatgt gcatcatcca ccgggatctg aactcgcaca actgcctcatcaagttggac 1500 aagactgtgg tggtggcaga ctttgggctg tcacggctca tagtggaagagaggaaaagg 1560 gcccccatgg agaaggccac caccaagaaa cgcaccttgc gcaagaacgaccgcaagaag 1620 cgctacacgg tggtgggaaa cccctactgg atggcccctg agatgctgaacggaaagagc 1680 tatgatgaga cggtggatat cttctccttt gggatcgttc tctgtgagatcattgggcag 1740 gtgtatgcag atcctgactg ccttccccga acactggact ttggcctcaacgtgaagctt 1800 ttctgggaga agtttgttcc cacagattgt cccccggcct tcttcccgctggccgccatc 1860 tgctgcagac tggagcctga gagcagacca gcattctcga aattggaggactcctttgag 1920 gccctctccc tgtacctggg ggagctgggc atcccgctgc ctgcagagctggaggagttg 1980 gaccacactg tgagcatgca gtacggcctg acccgggact cacctccctagccctggccc 2040 agccccctgc aggggggtgt tctacagcca gcattgcccc tctgtgccccattcctgctg 2100 tgagcagggc cgtccgggct tcctgtggat tggcggaatg tttagaagcagaacaagcca 2160 ttcctattac ctccccagga ggcaagtggg cgcagcacca gggaaatgtatctccacagg 2220 ttctggggcc tagttactgt ctgtaaatcc aatacttgcc tgaaagctgtgaagaagaaa 2280 aaaacccctg gcctttgggc caggaggaat ctgttactcg aatccacccaggaactccct 2340 ggcagtggat tgtgggaggc tcttgcttac actaatcagc gtgacctggacctgctgggc 2400 aggatcccag ggtgaacctg cctgtgaact ctgaagtcac tagtccagctgggtgcagga 2460 ggacttcaag tgtgtggacg aaagaaagac tgatggctca aagggtgtgaaaaagtcagt 2520 gatgctcccc ctttctactc cagatcctgt ccttcctgga gcaaggttgagggagtaggt 2580 tttgaagagt cccttaatat gtggtggaac aggccaggag ttagagaaagggctggcttc 2640 tgtttacctg ctcactggct ctagccagcc cagggaccac atcaatgtgagaggaagcct 2700 ccacctcatg ttttcaaact taatactgga gactggctga gaacttacggacaacatcct 2760 ttctgtctga aacaaacagt cacaagcaca ggaagaggct gggggactagaaagaggccc 2820 tgccctctag aaagctcaga tcttggcttc tgttactcat actcgggtgggctccttagt 2880 cagatgccta aaacattttg cctaaagctc gatgggttct ggaggacagtgtggcttgtc 2940 acaggcctag agtctgaggg aggggagtgg gagtctcagc aatctcttggtcttggcttc 3000 atggcaacca ctgctcaccc ttcaacatgc ctggtttagg cagcagcttgggctgggaag 3060 aggtggtggc agagtctcaa agctgagatg ctgagagaga tagctccctgagctgggcca 3120 tctgacttct acctcccatg tttgctctcc caactcatta gctcctgggcagcatcctcc 3180 tgagccacat gtgcaggtac tggaaaacct ccatcttggc tcccagagctctaggaactc 3240 ttcatcacaa ctagatttgc ctcttctaag tgtctatgag cttgcaccatatttaataaa 3300 ttgggaatgg gtttggggta ttaatgcaat gtgtggtggt tgtattggagcagggggaat 3360 tgataaagga gagtggttgc tgttaatatt atcttatcta ttgggtggtatgtgaaatat 3420 tgtacataga cctgatgagt tgtgggacca gatgtcatct ctggtcagagtttacttgct 3480 atatagactg tacttatgtg tgaagtttgc aagcttgctt tagggctgagccctggactc 3540 ccagcagcag cacagttcag cattgtgtgg ctggttgttt cctggctgtccccagcaagt 3600 gtaggagtgg tgggcctgaa ctgggccatt gatcagacta aataaattaagcagttaaca 3660 taactggc 3668 14 638 PRT Homo sapiens 14 Met Ser Ala LeuAla Gly Glu Asp Val Trp Arg Cys Pro Gly Cys Gly 1 5 10 15 Asp His IleAla Pro Ser Gln Ile Trp Tyr Arg Thr Val Asn Glu Thr 20 25 30 Trp His GlySer Cys Phe Arg Cys Ser Glu Cys Gln Asp Ser Leu Thr 35 40 45 Asn Trp TyrTyr Glu Lys Asp Gly Lys Leu Tyr Cys Pro Lys Asp Tyr 50 55 60 Trp Gly LysPhe Gly Glu Phe Cys His Gly Cys Ser Leu Leu Met Thr 65 70 75 80 Gly ProPhe Met Val Ala Gly Glu Phe Lys Tyr His Pro Glu Cys Phe 85 90 95 Ala CysMet Ser Cys Lys Val Ile Ile Glu Asp Gly Asp Ala Tyr Ala 100 105 110 LeuVal Gln His Ala Thr Leu Tyr Cys Gly Lys Cys His Asn Glu Val 115 120 125Val Leu Ala Pro Met Phe Glu Arg Leu Ser Thr Glu Ser Val Gln Glu 130 135140 Gln Leu Pro Tyr Ser Val Thr Leu Ile Ser Met Pro Ala Thr Thr Glu 145150 155 160 Gly Arg Arg Gly Phe Ser Val Ser Val Glu Ser Ala Cys Ser AsnTyr 165 170 175 Ala Thr Thr Val Gln Val Lys Glu Val Asn Arg Met His IleSer Pro 180 185 190 Asn Asn Arg Asn Ala Ile His Pro Gly Asp Arg Ile LeuGlu Ile Asn 195 200 205 Gly Thr Pro Val Arg Thr Leu Arg Val Glu Glu ValGlu Asp Ala Ile 210 215 220 Ser Gln Thr Ser Gln Thr Leu Gln Leu Leu IleGlu His Asp Pro Val 225 230 235 240 Ser Gln Arg Leu Asp Gln Leu Arg LeuGlu Ala Arg Leu Ala Pro His 245 250 255 Met Gln Asn Ala Gly His Pro HisAla Leu Ser Thr Leu Asp Thr Lys 260 265 270 Glu Asn Leu Glu Gly Thr LeuArg Arg Arg Ser Leu Arg Arg Ser Asn 275 280 285 Ser Ile Ser Lys Ser ProGly Pro Ser Ser Pro Lys Glu Pro Leu Leu 290 295 300 Phe Ser Arg Asp IleSer Arg Ser Glu Ser Leu Arg Cys Ser Ser Ser 305 310 315 320 Tyr Ser GlnGln Ile Phe Arg Pro Cys Asp Leu Ile His Gly Glu Val 325 330 335 Leu GlyLys Gly Phe Phe Gly Gln Ala Ile Lys Val Thr His Lys Ala 340 345 350 ThrGly Lys Val Met Val Met Lys Glu Leu Ile Arg Cys Asp Glu Glu 355 360 365Thr Gln Lys Thr Phe Leu Thr Glu Val Lys Val Met Arg Ser Leu Asp 370 375380 His Pro Asn Val Leu Lys Phe Ile Gly Val Leu Tyr Lys Asp Lys Lys 385390 395 400 Leu Asn Leu Leu Thr Glu Tyr Ile Glu Gly Gly Thr Leu Lys AspPhe 405 410 415 Leu Arg Ser Met Asp Pro Phe Pro Trp Gln Gln Lys Val ArgPhe Ala 420 425 430 Lys Gly Ile Ala Ser Gly Met Ala Tyr Leu His Ser MetCys Ile Ile 435 440 445 His Arg Asp Leu Asn Ser His Asn Cys Leu Ile LysLeu Asp Lys Thr 450 455 460 Val Val Val Ala Asp Phe Gly Leu Ser Arg LeuIle Val Glu Glu Arg 465 470 475 480 Lys Arg Ala Pro Met Glu Lys Ala ThrThr Lys Lys Arg Thr Leu Arg 485 490 495 Lys Asn Asp Arg Lys Lys Arg TyrThr Val Val Gly Asn Pro Tyr Trp 500 505 510 Met Ala Pro Glu Met Leu AsnGly Lys Ser Tyr Asp Glu Thr Val Asp 515 520 525 Ile Phe Ser Phe Gly IleVal Leu Cys Glu Ile Ile Gly Gln Val Tyr 530 535 540 Ala Asp Pro Asp CysLeu Pro Arg Thr Leu Asp Phe Gly Leu Asn Val 545 550 555 560 Lys Leu PheTrp Glu Lys Phe Val Pro Thr Asp Cys Pro Pro Ala Phe 565 570 575 Phe ProLeu Ala Ala Ile Cys Cys Arg Leu Glu Pro Glu Ser Arg Pro 580 585 590 AlaPhe Ser Lys Leu Glu Asp Ser Phe Glu Ala Leu Ser Leu Tyr Leu 595 600 605Gly Glu Leu Gly Ile Pro Leu Pro Ala Glu Leu Glu Glu Leu Asp His 610 615620 Thr Val Ser Met Gln Tyr Gly Leu Thr Arg Asp Ser Pro Pro 625 630 63515 2169 DNA Homo sapiens 15 ccgcctccga gtgccttgcg cggacctgag ctggagatgctggccgggct accgacgtca 60 gaccccgggc gcctcatcac ggacccgcgc agcggccgcacctacctcaa aggccgcttg 120 ttgggcaagg ggggcttcgc ccgctgctac gaggccactgacacagagac tggcagcgcc 180 tacgctgtca aagtcatccc gcagagccgc gtcgccaagccgcatcagcg cgagaagatc 240 ctaaatgaga ttgagctgca ccgagacctg cagcaccgccacatcgtgcg tttttcgcac 300 cactttgagg acgctgacaa catctacatt ttcttggagctctgcagccg aaagtccctg 360 gcccacatct ggaaggcccg gcacaccctg ttggagccagaagtgcgcta ctacctgcgg 420 cagatccttt ctggcctcaa gtacttgcac cagcgcggcatcttgcaccg ggacctcaag 480 ttgggaaatt ttttcatcac tgagaacatg gaactgaaggtgggggattt tgggctggca 540 gcccggttgg agcctccgga gcagaggaag aagaccatctgtggcacccc caactatgtg 600 gctccagaag tgctgctgag acagggccac ggccctgaagcggatgtatg gtcactgggc 660 tgtgtcatgt acacgctgct ctgcgggagc cctccctttgagacggctga cctgaaggag 720 acgtaccgct gcatcaagca ggttcactac acgctgcctgccagcctctc actgcctgcc 780 cggcagctcc tggccgccat ccttcgggcc tcaccccgagaccgcccctc tattgaccag 840 atcctgcgcc atgacttctt taccaagggc tacacccccgatcgactccc tatcagcagc 900 tgcgtgacag tcccagacct gacacccccc aacccagctaggagtctgtt tgccaaagtt 960 accaagagcc tctttggcag aaagaagaag agtaagaatcatgcccagga gagggatgag 1020 gtctccggtt tggtgagcgg cctcatgcgc acatccgttggccatcagga tgccaggcca 1080 gaggctccag cagcttctgg cccagcccct gtcagcctggtagagacagc acctgaagac 1140 agctcacccc gtgggacact ggcaagcagt ggagatggatttgaagaagg tctgactgtg 1200 gccacagtag tggagtcagc cctttgtgct ctgagaaattgtatagcttt catgccccca 1260 gcggaacaga acccggcccc cctggcccag ccagagcctctggtgtgggt cagcaagtgg 1320 gttgactact ccaataagtt cggctttggg tatcaactgtccagccgccg tgtggctgtg 1380 ctcttcaacg atggcacaca tatggccctg tcggccaacagaaagactgt gcactacaat 1440 cccaccagca caaagcactt ctccttctcc gtgggtgctgtgccccgggc cctgcagcct 1500 cagctgggta tcctgcggta cttcgcctcc tacatggagcagcacctcat gaagggtgga 1560 gatctgccca gtgtggaaga ggtagaggta cctgctccgcccttgctgct gcagtgggtc 1620 aagacggatc aggctctcct catgctgttt agtgatggcactgtccaggt gaacttctac 1680 ggggaccaca ccaagctgat tctcagtggc tgggagcccctccttgtgac ttttgtggcc 1740 cgaaatcgta gtgcttgtac ttacctcgct tcccaccttcggcagctggg ctgctctcca 1800 gacctgcggc agcgactccg ctatgctctg cgcctgctccgggaccgcag cccagcttag 1860 gacccaagcc ctgaaggcct gaggcctgtg cctgtcaggctctggccctt gcctttgtgg 1920 ccttccccct tcctttggtg cctcactggg ggctttgggccgaatccccc agggaatcag 1980 ggaccagctt tactggagtt gggggcggct tgtcttcgctggctcctacc ccatctccaa 2040 gataagcctg agccttagct cccagctagg gggcgttatttatggaccac ttttatttat 2100 tgtcagacac ttatttattg ggatgtgagc cccagggggcctcctcctag gataataaac 2160 aattttgca 2169 16 607 PRT Homo sapiens 16 MetLeu Ala Gly Leu Pro Thr Ser Asp Pro Gly Arg Leu Ile Thr Asp 1 5 10 15Pro Arg Ser Gly Arg Thr Tyr Leu Lys Gly Arg Leu Leu Gly Lys Gly 20 25 30Gly Phe Ala Arg Cys Tyr Glu Ala Thr Asp Thr Glu Thr Gly Ser Ala 35 40 45Tyr Ala Val Lys Val Ile Pro Gln Ser Arg Val Ala Lys Pro His Gln 50 55 60Arg Glu Lys Ile Leu Asn Glu Ile Glu Leu His Arg Asp Leu Gln His 65 70 7580 Arg His Ile Val Arg Phe Ser His His Phe Glu Asp Ala Asp Asn Ile 85 9095 Tyr Ile Phe Leu Glu Leu Cys Ser Arg Lys Ser Leu Ala His Ile Trp 100105 110 Lys Ala Arg His Thr Leu Leu Glu Pro Glu Val Arg Tyr Tyr Leu Arg115 120 125 Gln Ile Leu Ser Gly Leu Lys Tyr Leu His Gln Arg Gly Ile LeuHis 130 135 140 Arg Asp Leu Lys Leu Gly Asn Phe Phe Ile Thr Glu Asn MetGlu Leu 145 150 155 160 Lys Val Gly Asp Phe Gly Leu Ala Ala Arg Leu GluPro Pro Glu Gln 165 170 175 Arg Lys Lys Thr Ile Cys Gly Thr Pro Asn TyrVal Ala Pro Glu Val 180 185 190 Leu Leu Arg Gln Gly His Gly Pro Glu AlaAsp Val Trp Ser Leu Gly 195 200 205 Cys Val Met Tyr Thr Leu Leu Cys GlySer Pro Pro Phe Glu Thr Ala 210 215 220 Asp Leu Lys Glu Thr Tyr Arg CysIle Lys Gln Val His Tyr Thr Leu 225 230 235 240 Pro Ala Ser Leu Ser LeuPro Ala Arg Gln Leu Leu Ala Ala Ile Leu 245 250 255 Arg Ala Ser Pro ArgAsp Arg Pro Ser Ile Asp Gln Ile Leu Arg His 260 265 270 Asp Phe Phe ThrLys Gly Tyr Thr Pro Asp Arg Leu Pro Ile Ser Ser 275 280 285 Cys Val ThrVal Pro Asp Leu Thr Pro Pro Asn Pro Ala Arg Ser Leu 290 295 300 Phe AlaLys Val Thr Lys Ser Leu Phe Gly Arg Lys Lys Lys Ser Lys 305 310 315 320Asn His Ala Gln Glu Arg Asp Glu Val Ser Gly Leu Val Ser Gly Leu 325 330335 Met Arg Thr Ser Val Gly His Gln Asp Ala Arg Pro Glu Ala Pro Ala 340345 350 Ala Ser Gly Pro Ala Pro Val Ser Leu Val Glu Thr Ala Pro Glu Asp355 360 365 Ser Ser Pro Arg Gly Thr Leu Ala Ser Ser Gly Asp Gly Phe GluGlu 370 375 380 Gly Leu Thr Val Ala Thr Val Val Glu Ser Ala Leu Cys AlaLeu Arg 385 390 395 400 Asn Cys Ile Ala Phe Met Pro Pro Ala Glu Gln AsnPro Ala Pro Leu 405 410 415 Ala Gln Pro Glu Pro Leu Val Trp Val Ser LysTrp Val Asp Tyr Ser 420 425 430 Asn Lys Phe Gly Phe Gly Tyr Gln Leu SerSer Arg Arg Val Ala Val 435 440 445 Leu Phe Asn Asp Gly Thr His Met AlaLeu Ser Ala Asn Arg Lys Thr 450 455 460 Val His Tyr Asn Pro Thr Ser ThrLys His Phe Ser Phe Ser Val Gly 465 470 475 480 Ala Val Pro Arg Ala LeuGln Pro Gln Leu Gly Ile Leu Arg Tyr Phe 485 490 495 Ala Ser Tyr Met GluGln His Leu Met Lys Gly Gly Asp Leu Pro Ser 500 505 510 Val Glu Glu ValGlu Val Pro Ala Pro Pro Leu Leu Leu Gln Trp Val 515 520 525 Lys Thr AspGln Ala Leu Leu Met Leu Phe Ser Asp Gly Thr Val Gln 530 535 540 Val AsnPhe Tyr Gly Asp His Thr Lys Leu Ile Leu Ser Gly Trp Glu 545 550 555 560Pro Leu Leu Val Thr Phe Val Ala Arg Asn Arg Ser Ala Cys Thr Tyr 565 570575 Leu Ala Ser His Leu Arg Gln Leu Gly Cys Ser Pro Asp Leu Arg Gln 580585 590 Arg Leu Arg Tyr Ala Leu Arg Leu Leu Arg Asp Arg Ser Pro Ala 595600 605 17 3492 DNA Homo sapiens 17 cagctaagac ccggagaggt ggaatttcactttgaaattc ccttgcctcg tgagggccgg 60 cgctgggcat gctcagtagc cgcggcgctgctgctgggct gctgggctgg cgcggagtcc 120 accctgccgt ctccgccttg gcttctgggcgtccagaagg ccaggcattt gccgcctctg 180 agcgcttctg ttccccttac ccgcaacctcctactgctct tcctctctcc ctctcttagg 240 gaggttgaag ctggtgctgg tttctgtcggcgccacagac tgactgctct gcaaacccca 300 gccgaggacc tgaatcccgg agactagaagacccttggcg gtggctcttt ctaatagcac 360 tttacctgaa gtggggtcgt ggtggagtttctcctccacc tctcaatgca aacactatgc 420 ggagagcagt ctgcttccct gcgctgtgcctgctccttaa tcttcacgct gcagggtgct 480 tttcaggaaa caatgatcat tttttggcaattaatcagaa gaagagtggg aagccggtat 540 tcatttataa gcattcacaa gacattgagaagagcctgga tatagcccca caaaaaatct 600 acagacatag ctaccattcc tcttccgaagctcaagtaag caaacgccac cagattgtca 660 attcagcatt tcctagaccc gcatatgacccgtctctcaa tctgctggcc atggatggtc 720 aagatcttga agtggaaaat ctcccaatcccagcagcaaa tgtaattgtg gtgacactgc 780 aaatggatgt aaacaagctg aacataaccttgcttcggat cttccgccaa ggagtggctg 840 cagctttagg actcttaccc cagcaagtgcacatcaatcg cctcattgga aagaagaaca 900 gtattgaact gtttgtgtct cccataaaccgaaaaacagg aatttctgat gctctgccct 960 ctgaggaagt tcttcgttca cttaatatcaatgttttgca tcaaagttta tcccagtttg 1020 gaattacaga agtctctcct gagaaaaatgttttacaagg gcagcatgaa gcggacaaaa 1080 tctggagcaa agaaggattt tatgctgttgtcatttttct cagcatcttt gttattatag 1140 taacgtgttt gatgattctt tacagattaaaagaaagatt tcagctttcc ttaagacaag 1200 acaaagagaa aaaccaggag atccacctatcgcccatcac attacagcca gcactgtccg 1260 aggcaaagac agtccacagc atggtccaacctgagcaggc cccaaaggta ctgaatgttg 1320 tcgtggaccc tcaaggccga ggtgctcctgagatcagagc taccaccgct acctctgttt 1380 gcccttctcc tttcaaaatg aagcccataggacttcaaga gagaagaggg tccaacgtat 1440 ctcttacatt ggacatgagt agcttggggaacattgaacc ctttgtgtct ataccaacac 1500 cacgggagaa ggtagcaatg gagtatctgcagtcagccag ccgaattctc acaaggtctc 1560 agctgaggga cgtcgtggca agttcacatttactccaaag tgaattcatg gaaataccga 1620 tgaactttgt ggatcccaaa gaaattgatattccgcgtca tggaactaaa aatcgctata 1680 agaccatttt accaaatccc ctcagcagagtgtgtttaag accaaaaaat gtaaccgatt 1740 cattgagcac ctacattaat gctaattatattaggggcta cagtggcaag gagaaagcct 1800 tcattgccac gcagggcccc atgatcaacaccgtggatga tttctggcag atggtttggc 1860 aggaagacag ccctgtgatt gttatgatcacaaaactcaa agaaaaaaat gagaaatgtg 1920 tgctatactg gccggaaaag agagggatatatggaaaagt tgaggttctg gttatcagtg 1980 taaatgaatg tgataactac accattcgaaaccttgtctt aaagcaagga agccacaccc 2040 aacatgtgaa gcattactgg tacacctcatggcctgatca caagactcca gacagtgccc 2100 agcccctcct acagctcatg ctggatgtagaagaagacag acttgcttcc cagggccgag 2160 ggcctgtggt tgtccactgc agtgcaggaataggtagaac agggtgtttt attgctacat 2220 ccattggctg tcaacagctg aaagaagaaggagttgtgga tgcactaagc attgtctgcc 2280 agcttcgtat ggatagaggt ggaatggtccaaaccagtga gcagtatgaa tttgtgcacc 2340 atgctctgtg cctgtatgag agcagactttcagcagagac tgtccagtga gtcattgaag 2400 acttgtcaga ccatcaatct cttggggtgattaatcaaat tacccaccca aggcttctag 2460 aaggagcttc ctgcaatgga aggaaggagaagctctgaag cccatgtatg gcatggattg 2520 tggaagactg ggcaacatat ttaagatttccagctccttg tgtatatgaa tgcatttgta 2580 agcatccccc aaattattct gaaggttttttgatgatgga ggtatgatag gtttatcaca 2640 cagcctaagg cagattttgt tttgtctgtactgactctat ctgccacaca gaatgtatgt 2700 atgtaatatt cagtaataaa tgtcatcaggtgatgactgg atgagctgct gaagacattc 2760 gtattatgtg ttagatgctt taatgtttgcaaaatctgcc ttgtgaatgg actgtcagct 2820 gttaaactgt tcctgttttg aagtgctattacctttctca gttaccagaa tcttgctgct 2880 aaagttgcaa gtgattgata atggatttttaacagagaag tctttgtttt tgaaaaacaa 2940 aaatcaaaaa cagtaactat tttatatggaaatgtgtctt gataatatta cctattaaat 3000 gtgtatttat agtccctcct atcaaacaattacagagcac aatgattgtc attgggtata 3060 tatgtattta ctctctatta ttgggcataaaggtggcttc tgctccagaa ctctatccac 3120 tgtatttcca catcgtgagt cattttactttaaaagggaa aaacaaattt gtagcaactc 3180 tgaagtatca agagttttaa ctacttgactctcttttgct aagaagggat ttttgaatat 3240 gctatctacc tggaatctct ctctcaacaaaaggtatatg ccttcaggaa tgatataatc 3300 tgtcccattt tcgaggctcc ttataaggacatttccatgt atgtccttac atttctgaaa 3360 gctttcaatc ttcaagagcc aaaaaaaattaaaataacta ccctcagcaa acactagctg 3420 ttctgctcat atatgaattt ttaatgcagcaatgttgact ttgtttcata ctgccaataa 3480 actcttaata ct 3492 18 657 PRT Homosapiens 18 Met Arg Arg Ala Val Cys Phe Pro Ala Leu Cys Leu Leu Leu AsnLeu 1 5 10 15 His Ala Ala Gly Cys Phe Ser Gly Asn Asn Asp His Phe LeuAla Ile 20 25 30 Asn Gln Lys Lys Ser Gly Lys Pro Val Phe Ile Tyr Lys HisSer Gln 35 40 45 Asp Ile Glu Lys Ser Leu Asp Ile Ala Pro Gln Lys Ile TyrArg His 50 55 60 Ser Tyr His Ser Ser Ser Glu Ala Gln Val Ser Lys Arg HisGln Ile 65 70 75 80 Val Asn Ser Ala Phe Pro Arg Pro Ala Tyr Asp Pro SerLeu Asn Leu 85 90 95 Leu Ala Met Asp Gly Gln Asp Leu Glu Val Glu Asn LeuPro Ile Pro 100 105 110 Ala Ala Asn Val Ile Val Val Thr Leu Gln Met AspVal Asn Lys Leu 115 120 125 Asn Ile Thr Leu Leu Arg Ile Phe Arg Gln GlyVal Ala Ala Ala Leu 130 135 140 Gly Leu Leu Pro Gln Gln Val His Ile AsnArg Leu Ile Gly Lys Lys 145 150 155 160 Asn Ser Ile Glu Leu Phe Val SerPro Ile Asn Arg Lys Thr Gly Ile 165 170 175 Ser Asp Ala Leu Pro Ser GluGlu Val Leu Arg Ser Leu Asn Ile Asn 180 185 190 Val Leu His Gln Ser LeuSer Gln Phe Gly Ile Thr Glu Val Ser Pro 195 200 205 Glu Lys Asn Val LeuGln Gly Gln His Glu Ala Asp Lys Ile Trp Ser 210 215 220 Lys Glu Gly PheTyr Ala Val Val Ile Phe Leu Ser Ile Phe Val Ile 225 230 235 240 Ile ValThr Cys Leu Met Ile Leu Tyr Arg Leu Lys Glu Arg Phe Gln 245 250 255 LeuSer Leu Arg Gln Asp Lys Glu Lys Asn Gln Glu Ile His Leu Ser 260 265 270Pro Ile Thr Leu Gln Pro Ala Leu Ser Glu Ala Lys Thr Val His Ser 275 280285 Met Val Gln Pro Glu Gln Ala Pro Lys Val Leu Asn Val Val Val Asp 290295 300 Pro Gln Gly Arg Gly Ala Pro Glu Ile Arg Ala Thr Thr Ala Thr Ser305 310 315 320 Val Cys Pro Ser Pro Phe Lys Met Lys Pro Ile Gly Leu GlnGlu Arg 325 330 335 Arg Gly Ser Asn Val Ser Leu Thr Leu Asp Met Ser SerLeu Gly Asn 340 345 350 Ile Glu Pro Phe Val Ser Ile Pro Thr Pro Arg GluLys Val Ala Met 355 360 365 Glu Tyr Leu Gln Ser Ala Ser Arg Ile Leu ThrArg Ser Gln Leu Arg 370 375 380 Asp Val Val Ala Ser Ser His Leu Leu GlnSer Glu Phe Met Glu Ile 385 390 395 400 Pro Met Asn Phe Val Asp Pro LysGlu Ile Asp Ile Pro Arg His Gly 405 410 415 Thr Lys Asn Arg Tyr Lys ThrIle Leu Pro Asn Pro Leu Ser Arg Val 420 425 430 Cys Leu Arg Pro Lys AsnVal Thr Asp Ser Leu Ser Thr Tyr Ile Asn 435 440 445 Ala Asn Tyr Ile ArgGly Tyr Ser Gly Lys Glu Lys Ala Phe Ile Ala 450 455 460 Thr Gln Gly ProMet Ile Asn Thr Val Asp Asp Phe Trp Gln Met Val 465 470 475 480 Trp GlnGlu Asp Ser Pro Val Ile Val Met Ile Thr Lys Leu Lys Glu 485 490 495 LysAsn Glu Lys Cys Val Leu Tyr Trp Pro Glu Lys Arg Gly Ile Tyr 500 505 510Gly Lys Val Glu Val Leu Val Ile Ser Val Asn Glu Cys Asp Asn Tyr 515 520525 Thr Ile Arg Asn Leu Val Leu Lys Gln Gly Ser His Thr Gln His Val 530535 540 Lys His Tyr Trp Tyr Thr Ser Trp Pro Asp His Lys Thr Pro Asp Ser545 550 555 560 Ala Gln Pro Leu Leu Gln Leu Met Leu Asp Val Glu Glu AspArg Leu 565 570 575 Ala Ser Gln Gly Arg Gly Pro Val Val Val His Cys SerAla Gly Ile 580 585 590 Gly Arg Thr Gly Cys Phe Ile Ala Thr Ser Ile GlyCys Gln Gln Leu 595 600 605 Lys Glu Glu Gly Val Val Asp Ala Leu Ser IleVal Cys Gln Leu Arg 610 615 620 Met Asp Arg Gly Gly Met Val Gln Thr SerGlu Gln Tyr Glu Phe Val 625 630 635 640 His His Ala Leu Cys Leu Tyr GluSer Arg Leu Ser Ala Glu Thr Val 645 650 655 Gln 19 985 DNA Homo sapiens19 ccggcccggt gtggctgtgc cgttggtcct gtgcggtcac ttagccaaga tgcctgagga 60aacccagacc caagaccaac cgatggagga ggaggaggtt gagacgttcg cctttcaggc 120agaaattgcc cagttgatgt cattgatcat caatactttc tactcgaaca aagagatctt 180tctgagagag ctcatttcaa attcatcaga tgcattggac aaaatccggt atgaaagctt 240gacagatccc agtaaattag actctgggaa agagctgcat attaacctta taccgaacaa 300acaagatcga actctcacta ttgtggatac tggaattgga atgaccaagg ctgacttgat 360caataacctt ggtactatcg ccaagtctgg gaccaaagcg ttcatggaag ctttgcaggc 420tggtgcagat atctctatga ttggccagtt cggtgttggt ttttattctg cttatttggt 480tgctgagaaa gtaactgtga tcaccaaaca taacgatgat gagcagtacg cttgggagtc 540ctcagcaggg ggatcattca cagtgaggac agacacaggt gaacctatgg gtcgtggaac 600aaaagttatc ctacacctga aagaagacca aactgagtac ttggaggaac gaagaataaa 660ggagattgtg aagaaacatt ctcagtttat tggatatccc attactcttt ttgtggagaa 720ggaacgtgat aaagaagtaa gcgatgatga ggctgaagaa aaggaagaca aagaagaaga 780aaaagaaaaa gaagagaaag agtcggaaga caaacctgaa attgaagatg ttggttctga 840tgaggaagaa gaaaagaagg atggtgacaa gaagaagaag aagaagatta aggaaaagta 900catcgatcaa gaagagctca acaaaacaaa gcccatctgg accagaaatc ccgacgatat 960tactaatgag gagtacggag aattc 985 20 312 PRT Homo sapiens 20 Met Pro GluGlu Thr Gln Thr Gln Asp Gln Pro Met Glu Glu Glu Glu 1 5 10 15 Val GluThr Phe Ala Phe Gln Ala Glu Ile Ala Gln Leu Met Ser Leu 20 25 30 Ile IleAsn Thr Phe Tyr Ser Asn Lys Glu Ile Phe Leu Arg Glu Leu 35 40 45 Ile SerAsn Ser Ser Asp Ala Leu Asp Lys Ile Arg Tyr Glu Ser Leu 50 55 60 Thr AspPro Ser Lys Leu Asp Ser Gly Lys Glu Leu His Ile Asn Leu 65 70 75 80 IlePro Asn Lys Gln Asp Arg Thr Leu Thr Ile Val Asp Thr Gly Ile 85 90 95 GlyMet Thr Lys Ala Asp Leu Ile Asn Asn Leu Gly Thr Ile Ala Lys 100 105 110Ser Gly Thr Lys Ala Phe Met Glu Ala Leu Gln Ala Gly Ala Asp Ile 115 120125 Ser Met Ile Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Tyr Leu Val 130135 140 Ala Glu Lys Val Thr Val Ile Thr Lys His Asn Asp Asp Glu Gln Tyr145 150 155 160 Ala Trp Glu Ser Ser Ala Gly Gly Ser Phe Thr Val Arg ThrAsp Thr 165 170 175 Gly Glu Pro Met Gly Arg Gly Thr Lys Val Ile Leu HisLeu Lys Glu 180 185 190 Asp Gln Thr Glu Tyr Leu Glu Glu Arg Arg Ile LysGlu Ile Val Lys 195 200 205 Lys His Ser Gln Phe Ile Gly Tyr Pro Ile ThrLeu Phe Val Glu Lys 210 215 220 Glu Arg Asp Lys Glu Val Ser Asp Asp GluAla Glu Glu Lys Glu Asp 225 230 235 240 Lys Glu Glu Glu Lys Glu Lys GluGlu Lys Glu Ser Glu Asp Lys Pro 245 250 255 Glu Ile Glu Asp Val Gly SerAsp Glu Glu Glu Glu Lys Lys Asp Gly 260 265 270 Asp Lys Lys Lys Lys LysLys Ile Lys Glu Lys Tyr Ile Asp Gln Glu 275 280 285 Glu Leu Asn Lys ThrLys Pro Ile Trp Thr Arg Asn Pro Asp Asp Ile 290 295 300 Thr Asn Glu GluTyr Gly Glu Phe 305 310

1. Compounds having the general formula (I):

wherein: R represents hydrogen or methyl; Y, Y′, Y″ are independently ofeach other —H, —F, —Cl, —Br, —I, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —OH,—OCH₃, —CH₃, —CN, —OCF₃, 4-methylpiperazin-1-yl-methyl,—C(CH₃)═N—NH—C(NH)—NH₂; Z represents —NO₂, —NH₂, —NH—CO—X, —NH—CS—X,—NH—CO—NH—X, —NH—SO₂—X; X represents thiophenyl, cyclohexyl,isoquinolinyl, naphthyl, quinolinyl, cyclopentyl, pyridinyl,naphthyridinyl, or

and pharmaceutically acceptable salts thereof.
 2. Use of a compoundhaving the general formula (I):

wherein: R represents hydrogen or methyl; Y, Y′, Y″ are independently ofeach other —H, —F, —Cl, —Br, —I, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —OH,—OCH₃, —CH₃, —CN, —OCF₃, 4-methylpiperazin-1-yl-methyl,—C(CH₃)═N—NH—C(NH)—NH₂; Z represents —NO₂, —NH₂, —NH—CO—X, —NH—CS—X,—NH—CO—NH—X, —NH—SO₂—X; X represents thiophenyl, cyclohexyl,isoquinolinyl, naphthyl, quinolinyl, cyclopentyl, pyridinyl,naphthyridinyl, or

and pharmaceutically acceptable salts thereof as pharmaceutically activeagents.
 3. Use of a compound having the general formula (I):

wherein: R represents hydrogen or methyl; Y, Y′, Y″ are independently ofeach other —H, —F, —Cl, —Br, —I, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —OH,—OCH₃, —CH₃, —CN, —OCF₃, 4-methylpiperazin-1-yl-methyl,—C(CH₃)═N—NH—C(NH)—NH₂; Z represents —NO₂, —NH₂, —NH—CO—X, —NH—CS—X,—NH—CO—NH—X, —NH—SO₂—X; X represents thiophenyl, cyclohexyl,isoquinolinyl, naphthyl, quinolinyl, cyclopentyl, pyridinyl,naphthyridinyl, or

and pharmaceutically acceptable salts thereof for prophylaxis and/ortreatment of infectious diseases or neurodegenerative diseases.
 4. Useof a compound according to claim 2 or 3 for the prophylaxis and/ortreatment of prion infections and/or diseases induced by prioninfection.
 5. Use of a compound according to any one of claims 2-4wherein R represents hydrogen.
 6. Use of a compound according to any oneof claims 2-5 wherein Z represents —NH—CO—X or —NH—SO₂—X.
 7. Use of acompound according to any one of claims 2-6 wherein Y, Y′, Y″ areindependently of each other —H, —F, —Cl, —CH₂F, —CH₂Cl, —OH, —OCH₃,—CH₃, —CN, —OCF₃, 4-methylpiperazin-1-yl-methyl.
 8. Use of a compoundaccording to claim 2 or 3 wherein the compound is selected from thegroup comprising: (3-Nitrophenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine;(3-Aminophenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine;(5-Amino-2-methylphenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine;4-Chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloromethyl-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-(4-Methylpiperazin-1-ylmethyl)-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Thiophene-3-carboxylic acid[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-pheny]-amide;4-Chloro-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,4,5-Trimethoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Cyano-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;Thiophene-3-carboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;3,5-Dimethoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Cyano-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;Thiophene-3-carboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Trifluoromethoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Cyclohexanecarboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;Cyclohexanecarboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;Isoquinoline-5-sulfonic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;Isoquinoline-5-sulfonic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;(5-Nitro-2-methylphenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;(5-Amino-2-methylphenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Cyano-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;(3-Aminophenyl)-(4-pyridin-2-yl-pyrimidin-2-yl)-amine;4-Chloro-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Cyclohexanecarboxylic acid[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-amide;4-Cyano-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;4-Methoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Cyclohexanecarboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;3,5-Dimethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;(5-Amino-2-methylphenyl)-(4-pyridin-4-pyrimidin-2-yl)-amine;Thiophene-3-carboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;4-Chloro-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;4-Chloro-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;(3-Aminophenyl)-(4-pyridin-4-yl-pyrimidin-2-yl)-amine;(3-Nitrophenyl)-(4-pyridin-4-yl-pyrimidin-2-yl)-amine;4-Trifluoromethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Isoquinoline-5-sulfonic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;4-Methoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4Cyano-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,4,5-Trimethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,4,5-Trimethoxy-N-[4-methyl-3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;4-Methoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,5-Dimethoxy-N-[4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Naphthalene-2-carboxylic acid[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;N-[3-(4-Pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methoxy-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;Thiophene-2-carboxylic acid3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;Naphthalene-2-sulfonic-acid[3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;Isoquinoline-5-sulfonic-acid[3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;Cylopentanecarboxylic acid3-(4-pyridin-2-yl-pyrimidin-2-yl-amino)-phenyl]-amide;Naphthalene-2carboxylic acid[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-amide;4-Cyano-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;3,5-Dimethoxy-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Bromo-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Fluoro-N-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;3,5-Dichloro-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;N-[3-(4-Pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Chloromethyl-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzenesulfonamide;4-(4-Methylpiperazin-1-ylmethyl)-N-[3-(4-pyridin-2-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;Naphthalene-2-carboxylic acid[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-amide;2-Methoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;2-Methoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;1(3,5-Diacetyl-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny]-urea;1-{3,5-Bis-(amidinohydrazone)-phenyl}-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-urea;N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-nicotinamide;N-[3-(4-Pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-nicotinamide;[1,8]Naphthyridine-2carboxylic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;[1,8]Naphthyridine-2carbothioic acid[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-amide;2-Methoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Trifluoromethoxy-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;4-Methyl-N-[3-(4-pyridin-4-yl-pyrimidin-2-ylamino)-phenyl]-benzamide;and/or a pharmaceutically acceptable salt of these compounds.
 9. Useaccording to claim 8 wherein the compound is4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide.10. Use of a compound recited in any one of claims 2-9 and/orpharmaceutically acceptable salts thereof for the manufacture of apharmaceutical composition for prophylaxis and/or treatment of prioninfections and/or diseases induced by prion infection and/orneurodegenerative diseases.
 11. Use according to claim 4 or 10 whereinsaid prion infection and/or disease is selected from the groupcomprising Scrapie, TME, CWD, BSE, CJD, vCJD, GSS, FFI, Kuru, and AlpersSyndrome.
 12. Use according to claim 11 wherein said prion infection isBSE, vCJD, or CJD.
 13. Use of a compound recited in any one of claims2-9 as an inhibitor for at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.
 14. Use of a compoundaccording to any one of claims 2 to 13 wherein the compound of thegeneral formula (I) and/or pharmaceutically acceptable salts thereof isadministered in a dosage corresponding to an effective concentration inthe range of 0.01-50 μM.
 15. Pharmaceutical composition comprising atleast one compound recited in any one of claims 2-9 as an activeingredient, together with one or more pharmaceutically acceptablecarrier(s), excipient(s) or diluents.
 16. Method for preventing and/ortreating infections and/or diseases in an individual which comprisesadministering to the individual an amount of at least one compoundrecited in claims 2-9 and/or pharmaceutically acceptable salts thereofeffective to prevent and/or treat said infections and/or diseases. 17.Method for preventing and/or treating prion infections and/or priondiseases induced by prion infections in an individual which comprisesadministering to the individual an amount of at least one compoundrecited in any one of claims 3 to 8 and/or pharmaceutically acceptablesalts thereof effective to prevent and/or treat said prion infectionand/or disease.
 18. Method for preventing and/or treating prioninfections and/or prion diseases induced by prion infections in anindividual which comprises administering to the individual an amount ofat least one compound recited in claim 8 and/or pharmaceuticallyacceptable salts thereof effective to prevent and/or treat said prioninfection and/or disease.
 19. Method for detecting prion infectionsand/or prion diseases in an individual comprising: a) providing a samplefrom said individual; b) adding to said sample a pharmaceuticallyeffective amount of at least one pharmaceutically active agent; and c)detecting activity in said sample of at least one human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.
 20. Method accordingto claim 19 wherein said sample comprises blood, milk, saliva, sputum,excrement, urine, spinal cord liquid, liquor, lachrymal gland liquid,biopsies and all other samples that can be taken from a living animal orhuman for diagnostic purposes.
 21. Method for detecting prion infectionsand/or prion diseases in cells, cell cultures and/or cell lysatescomprising: a) providing said cells, cell cultures and/or cell lysates;b) adding to said cells, cell cultures and/or cell lysates apharmaceutically effective amount of at least one pharmaceuticallyactive agent; and c) detecting activity in said sample of at least onehuman cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, GPIR-1.
 22. Method for preventing and/or treating prioninfections and/or prion diseases in an individual comprising the step ofadministering a pharmaceutically effective amount of at least onepharmaceutically active agent which inhibits at least partially theactivity of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1, or which inhibits at least partially theproduction of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1.
 23. Method for preventing and/or treating prioninfections and/or prion diseases in cell or cell cultures comprising thestep of administering a pharmaceutically effective amount of at leastone pharmaceutically active agent which inhibits at least partially theactivity of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1, or which inhibits at least partially theproduction of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, GPIR-1.
 24. Method for regulating the production ofprions in an individual comprising the step of administering apharmaceutically effective amount of at least one pharmaceuticallyactive agent which inhibits at least partially the activity of at leastone human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, GPIR-1, or which inhibits at least partially the production of atleast one human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, GPIR-1.
 25. Method for regulating the production of prions incells comprising the step of administering a pharmaceutically effectiveamount of at least one pharmaceutically active agent which inhibits atleast partially the activity of at least one human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1, or which inhibits atleast partially the production of at least one human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1.
 26. A monoclonal orpolyclonal antibody that binds to a human cellular protein kinase,phosphatase or a cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 27. Method according toany one of claims 19-25, wherein the agent is a monoclonal or polyclonalantibody which binds to a human cellular protein kinase, phosphatase ora cellular signal transduction molecule selected from the groupcomprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2,PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 28. Method according to anyone of claims 19-25, wherein the agent is at least one compound of thegeneral formula (I) and/or pharmaceutically acceptable salts thereof.29. Method according to any one of claims 16-25, wherein the agent is4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl-amino)-phenyl]-benzamideand/or pharmaceutically acceptable salts thereof.
 30. Method accordingto claim 28 wherein the compound of the general formula (I) and/orpharmaceutically acceptable salts thereof is administered in a dosagecorresponding to an effective concentration in the range of 0.01-50 μM.31. Method for detecting compounds useful for the prophylaxis and/ortreatment of prion infections and/or diseases comprising: a) contactinga test compound with at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, GPIR-1; and b) detecting theactivity of said human cellular protein kinase, phosphatase or cellularsignal transduction molecule.
 32. Method for preventing and/or treatingprion infections and/or diseases in an individual comprising the step ofadministering a pharmaceutically effective amount of at least onepharmaceutically active agent which activates at least partially theactivity of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1, or which activates or stimulates theproduction of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1.
 33. Method for regulating the production ofprions in an individual comprising the step of administering anindividual a pharmaceutically effective amount of at least onepharmaceutically active agent wherein said agent activates at leastpartially the activity of at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1, or wherein said agent atleast partially activates or stimulates the production of at least onehuman cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1.
 34. Method for regulating the production of prions incells comprising the step of administering the cells a pharmaceuticallyeffective amount of at least one pharmaceutically active agent whereinsaid agent activates at least partially the activity of at least onehuman cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1 or wherein said agent at least partially activates orstimulates the production of at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1 in the cells.
 35. Methodfor regulating the expression of at least one human cellular proteinkinase, phosphatase or cellular signal transduction molecule selectedfrom the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI,JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1 in an individualcomprising the step of administering the individual a pharmaceuticallyeffective amount of at least one pharmaceutically active agent whereinsaid agent inhibits at least partially the transcription of DNA or thetranslation of RNA.
 36. Method for regulating the expression of at leastone human cellular protein kinase, phosphatase or cellular signaltransduction molecule selected from the group comprising FGF-R1, Tkt,Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta,HSP86, and GPIR-1 in the cells comprising the step of administering thecells a pharmaceutically effective amount of at least onepharmaceutically active agent wherein said agent inhibits at leastpartially the transcription of DNA or the translation of RNA. 37.Oligonucleotide that binds to the DNA or RNA encoding a human cellularprotein kinase, phosphatase or a cellular signal transduction moleculeselected from the group comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2,CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 38. Methodaccording to claim 22, 23, 24, 25, 35 or 36 wherein the agent is aoligonucleotide which binds to the DNA and/or RNA encoding a humancellular protein kinase, phosphatase or a cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, andGPIR-1.
 39. Method according to claims 16, 17, 18, 19, 22, 24, 32, 33,or 35 wherein said individual is a human or ruminant.
 40. Methodaccording to any one of claims 17, 18, 19, 21, 22, 23, 31, or 32 whereinsaid prion infection and/or prion disease is selected from the groupcomprising Scrapie, TME, CWD, BSE, vCJD, CJD, GSS, FFI, Kuru, and AlpersSyndrome.
 41. Method according to claim 40 wherein said prion infectionand/or prion disease is BSE, vCJD, or CJD.
 42. A solid support usefulfor detecting prion infections and/or diseases in an individual, thesolid support comprising an immobilized oligonucleotide, wherein saidoligonucleotide is capable of detecting activity of at least one humancellular protein kinase, phosphatase or cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, andGPIR-1.
 43. A solid support useful for detecting prion infections and/ordiseases in cells, the solid support comprising an immobilizedoligonucleotide, wherein said oligonucleotide is capable of detectingactivity of at least one human cellular protein kinase, phosphatase orcellular signal transduction molecule selected from the group comprisingFGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL,PTP-zeta, HSP86, and GPIR-1.
 44. A solid support useful for screeningcompounds useful for the prophylaxis and/or treatment of prioninfections and/or diseases in an individual, the solid supportcomprising at least one immobilized oligonucleotide, wherein saidoligonucleotide encodes one human cellular protein kinase, phosphataseor cellular signal transduction molecule selected from the groupcomprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2, CDC2,PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 45. A solid support useful forscreening compounds useful for the prophylaxis and/or treatment of prioninfections and/or diseases in an individual, the solid supportcomprising at least one immobilized human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 46. Composition usefulfor the prophylaxis and/or treatment of an individual afflicted withprions comprising at least one agent capable of inhibiting at leastpartially the activity of at least one human cellular protein kinase,phosphatase or cellular signal transduction molecule selected from thegroup comprising FGF-R1, Tkt, Abl, clk1, MKK7, LIMK-2, CaM-KI, JNK2,CDC2, PRK, PTP-SL, PTP-zeta, HSP86, and GPIR-1.
 47. Composition usefulfor the prophylaxis and/or treatment of an individual afflicted withprions comprising at least one agent capable of activating orstimulating at least partially the activity of at least one humancellular protein kinase, phosphatase or cellular signal transductionmolecule selected from the group comprising FGF-R1, Tkt, Abl, clk1,MKK7, LIMK-2, CaM-KI, JNK2, CDC2, PRK, PTP-SL, PTP-zeta, HSP86, andGPIR-1.
 48. Composition according claim 46 or 47, wherein the agent isat least one compound of the general formula (I) and/or pharmaceuticallyacceptable salts thereof.